Sulfonic acid derivatives of hydroxamic acids and their use as medicinal products

ABSTRACT

The present invention relates to a novel sulfonic acid derivative of hydroxamic acid or a pharmacologically acceptable salt thereof. More particularly, the present invention relates to a sulfonic acid derivative of hydroxamic acid or a pharmacologically acceptable salt thereof, which is useful as an inhibitor of lipopolysaccharides (LPS). In addition, the present invention relates to a novel intermediate compound useful for the synthesis of this sulfonic acid derivative of hydroxamic acid.

TECHNICAL FIELD

[0001] The present invention relates to a novel sulfonic acid derivativeof hydroxamic acid or a pharmacologically acceptable salt thereof. Moreparticularly, the present invention relates to a sulfonic acidderivative of hydroxamic acid or a pharmacologically acceptable saltthereof, which is useful as an inhibitor of lipopolysaccharides (LPS).Furthermore, the present invention relates to a novel intermediatecompound useful for the synthesis of the above-mentioned sulfonic acidderivative of hydroxamic acid.

BACKGROUND ART

[0002] Sepsis is defined as a systemic inflammatory response syndromeassociated with infection [Bone RC: Ann. Intern. Med. 115, 457(1991)],and first begins with an excess invasion of Gram-negative bacteria, thatare causative bacteria of sepsis, or an endotoxin, which is a cell wallconstituent component thereof, from a primary lesion into the blood, anddistribution thereof throughout the body via the circulatory system. Theendotoxin is a lipopolysaccharide (LPS) present in bacterial outermembrane, which is released by the death of Gram-negative bacteria. Itstimulates inflammatory cells such as macrophage, neutrophil, lymphocyteand the like and vascular endothelial cell in an organism to causeproduction of inflammatory cytokines (IL-1, IL-6, IL-8 and the like)including TNF _(α) (tumor necrosis factor _(α)). Such remarkableincrease in the inflammatory cytokines causes severe multiple organdysfunction syndrome (MODS) and often results in the death of organisms.

[0003] The chemotherapy of sepsis essentially requires the first use ofantibiotics for the eradication of infectious bacteria. In General,administration of antibiotics is most commonly used in parallel withchemotherapy or surgical treatment of complications, in view of the highprobability of sequential complications [Fujii et al., Pharmaceuticalagent Journal, 34, 1501(1998)]. As is clear from the fact that lethalitydue to sepsis has not decreased since 1980s, however, these treatmentmethods are considered to have reached the limit.

[0004] In recent years, anti-cytokine therapies targeting inflammatorycytokines such as TNF _(α) and the like have been actively tried as anew sepsis treatment method. However, effectiveness thereof has not beenconfirmed in clinical tests of TNF _(α) neutralizing antibody, solubleTNF _(α) receptor and IL-1 receptor antagonist and the like [GouWakabayashi et al.,, Igaku no Ayumi Bessatsu, 108 (1998)]. The targetedinflammatory cytokine is considered to be harmful when it exists inexcess but necessary for biological protection as long as it is producedin a certain level of amount.

[0005] That is, it means that a complete control of biological activityof cytokine may conversely exacerbate the lesion depending on the stagesof disease state of septic patients, which is considered to have beenreflected in these clinical achievements [Masahiko Hirota et al., NihonGekagakkai Zasshi 100: 667-673 (1999), Gou Wakabayashi et al., NihonGekagakkai Zasshi 100: 674-678 (1999)].

[0006] In addition, while the endotoxin removing column developed as amedical material has been confirmed to be clinically effective [KazuhikoHanazawa et al., ICU and CCU, 197 (1999)], it is expensive and usethereof within the range insurance policy can cover is limited. Theforegoing facts suggest importance of endotoxin in the disease state ofsepsis, and teach that a low-molecular compound that inhibits endotoxinper se located at the upstream of various inflammatory cytokinesincluding TNF _(α) is a promising new agent for the prophylaxis ortreatment of sepsis.

[0007] Heretofore, hydroxamic acid derivatives have been studied as MMP(matrix metalloproteinase) inhibitors, and many of such inhibitors havebeen reported to have an inhibitory action on inflammatory cytokines,particularly TNF _(α). Many of these have been studied as an agent forthe prophylaxis or treatment of sepsis (e.g., WO94/10990 etc.), but havenot been clinically applied. In addition, an endotoxin (LPS) inhibitoryaction by hydroxamic acid derivative has not been reported heretofore.

[0008] The present invention has been made in view of theabove-mentioned background art, and aims at providing a novel sulfonicacid derivative of hydroxamic acid useful as an LPS inhibitor, and apharmacologically acceptable salt thereof.

[0009] Another object of the present invention is to provide a novelintermediate compound useful for the synthesis of said compound.

[0010] A yet another object of the present invention is to provide anovel LPS inhibitor useful as a pharmaceutical agent.

DISCLOSURE OF THE INVENTION

[0011] The present inventors have found that a sulfonic acid derivativeof hydroxamic acid or a pharmacologically acceptable salt thereof has anLPS inhibitory action, and further found that the compound of thepresent invention inhibits an increase of LPS in animal models, too,which resulted in the completion of the present invention.

[0012] Accordingly, the present invention provides the following.

[0013] (1) A sulfonic acid derivative of hydroxamic acid of the formula(I)

[0014] wherein

[0015] X is hydrogen or a hydroxyl group-protecting group;

[0016] R¹ is hydrogen, alkyl, arylalkyl, heteroarylalkyl,heteroarylalkylthioalkyl, heteroarylthioalkyl, arylthioalkyl,alkylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, alkenyl, or—(CH₂)₁-A [1 is an integer of any of 1 to 4 and A is anitrogen-containing 5- or 6-membered hetero ring which (a) is bonded viaa nitrogen atom, (b) may contain, as a further hetero atom, at least onekind of atom selected from nitrogen, oxygen and sulfur at a position notadjacent to the bonded nitrogen atom, (c) contains carbon atoms adjacentto the bonded nitrogen atom, one or both of which is(are) substituted byoxo, and which (d) is benzocondensed or has one or more other carbonatoms optionally substituted by lower alkyl or oxo, and/or has othernitrogen atom optionally substituted by lower alkyl or phenyl];

[0017] R² is hydrogen, alkyl, arylalkyl, heteroarylalkyl, cycloalkyl,cycloalkylalkyl or aryl;

[0018] Y is O, NR⁷ (R⁷ is as defined for R²) or S;

[0019] n is an integer of any of 1 to 6;

[0020] R³ is hydrogen, halogen (fluorine, chlorine, bromine, iodine),hydroxyl group, trifluoromethyl, cyano, nitro, amino, alkyl, alkoxy,acyloxy, carbamoyl, lower alkylamino or dilower alkylamino group;

[0021] R⁴ is OR⁸ (R⁸ is hydrogen, lower alkyl, aryl, heteroaryl,arylalkyl or heteroarylalkyl) or NR¹⁰ R¹¹ [R¹⁰ and R¹¹ are the same ordifferent and each is hydrogen, lower alkyl, arylalkyl, heteroaryl,heteroarylalkyl or aryl, or R¹⁰ and R¹¹ may form an optionallysubstituted hetero ring together with the adjacent nitrogen atom]; and

[0022] the aforementioned arylalkyl, heteroarylalkyl,heteroarylalkylthioalkyl, heteroarylthioalkyl, arylthioalkyl,arylalkylthioalkyl, phthalimidoalkyl, aryl and heteroaryl optionallyhave substituents,

[0023] or a pharmacologically acceptable salt thereof,

[0024] (2) the sulfonic acid derivative of hydroxamic acid of theabove-mentioned (1), wherein R³ is hydrogen or a pharmacologicallyacceptable salt thereof,

[0025] (3) the sulfonic acid derivative of hydroxamic acid of theabove-mentioned (1) or (2), wherein R⁴ is NHCH₃ or NHC₆H₅, or apharmacologically acceptable salt thereof,

[0026] (4) A sulfonic acid derivative of hydroxamic acid of the formula(II)

[0027] wherein

[0028] X is hydrogen or a hydroxyl group-protecting group;

[0029] R¹ is hydrogen, alkyl, arylalkyl, heteroarylalkyl,heteroarylalkylthioalkyl, heteroarylthioalkyl, arylthioalkyl,alkylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, alkenyl, or—(CH₂)₁-A [1 is an integer of any of 1 to 4 and A is anitrogen-containing 5- or 6-membered hetero ring which (a) is bonded viaa nitrogen atom, (b) may contain, as a further hetero atom, at least onekind of atom selected from nitrogen, oxygen and sulfur at a position notadjacent to the bonded nitrogen atom, (c) contains carbon atoms adjacentto the bonded nitrogen atom, one or both of which is(are) substituted byoxo, and which (d) is benzocondensed or has one or more other carbonatoms optionally substituted by lower alkyl or oxo, and/or has othernitrogen atom optionally substituted by lower alkyl or phenyl];

[0030] R² is hydrogen, alkyl, arylalkyl, heteroarylalkyl, cycloalkyl,cycloalkylalkyl or aryl;

[0031] R¹² is a characteristic group of natural or non-natural_(α)-amino acid, wherein a functional group present therein may beprotected;

[0032] R⁶ is hydrogen, lower alkyl, aryl, heteroaryl, arylalkyl orheteroarylalkyl;

[0033] Z is alkylene having 1 to 6 carbon atoms, phenylene ornaphthalene; and

[0034] the aforementioned arylalkyl, heteroarylalkyl,heteroarylalkylthioalkyl, heteroarylthioalkyl, arylthioalkyl,arylalkylthioalkyl, phthalimidoalkyl, aryl and heteroaryl optionallyhave substituents,

[0035] or a pharmacologically acceptable salt thereof,

[0036] (5) the sulfonic acid derivative of hydroxamic acid of theabove-mentioned (4), wherein R¹² is benzyl, or a pharmacologicallyacceptable salt thereof,

[0037] (6) the sulfonic acid derivative of hydroxamic acid of theabove-mentioned (4) or (5), wherein R⁶ is hydrogen, or apharmacologically acceptable salt thereof,

[0038] (7) the sulfonic acid derivative of hydroxamic acid of any of theabove-mentioned (1) to (6), wherein R¹ is phthalimidomethyl, or apharmacologically acceptable salt thereof,

[0039] (8) the sulfonic acid derivative of hydroxamic acid of any of theabove-mentioned (1) to (7), wherein R² is isobutyl, or apharmacologically acceptable salt thereof,

[0040] (9) a sulfonic acid derivative of hydroxamic acid selected fromthe group consisting of5-methyl-3(R)-[1(S)-methylcarbamoyl-2-(4-sulfomethoxyphenyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid,

[0041]5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(2-sulfoethoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid,

[0042]5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid,

[0043]5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(4-sulfobutoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid,

[0044]5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(5-sulfopentoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexano hydroxamic acid,

[0045]5-methyl-3(R)-[1(S)-methylcarbamoyl-2-(4-sulfomethoxyphenyl)ethylcarbamoyl]-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic acid,

[0046]5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(2-sulfoethoxy)phenyl]ethylcarbamoyl}-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic acid,

[0047]5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic acid,

[0048]5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(4-sulfobutoxy)phenyl]ethylcarbamoyl}-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic acid,

[0049]5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(5-sulfopentoxy)phenyl]ethylcarbamoyl}-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic acid,

[0050]5-methyl-3(R)-{1(S)-phenylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid,

[0051]5-methyl-3(R)-[2-phenyl-1(S)-(sulfomethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid,

[0052]5-methyl-3(R)-[2-phenyl-1(S)-(2-sulfoethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid,

[0053]5-methyl-3(R)-[2-phenyl-1(S)-(3-sulfopropylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid,

[0054]5-methyl-3(R)-[2-phenyl-1(S)-(4-sulfobutylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid,

[0055]5-methyl-3(R)-[2-phenyl-1(S)-(5-sulfopentylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid,

[0056] 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(sulfomethylcarbamoyl)ethylcarbamoyl]hexanohydroxamicacid,

[0057] 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(2-sulfoethylcarbamoyl)ethylcarbamoyl]hexanohydroxamicacid,

[0058] 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(3-sulfopropylcarbamoyl)ethylcarbamoyl]hexanohydroxamicacid,

[0059] 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(4-sulfobutylcarbamoyl)ethylcarbamoyl]hexanohydroxamicacid,

[0060] 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(5-sulfopentylcarbamoyl)ethylcarbamoyl]hexanohydroxamicacid and

[0061]5-methyl-3(R)-[2-phenyl-1(S)-(4-sulfophenylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid, or a pharmacologicallyacceptable salt thereof,

[0062] (10) a compound of the formula (III)

[0063] wherein

[0064] R⁹ is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl;

[0065]

is a single bond or double bond;

[0066] R¹³ is, when

is a single bond, hydrogen, alkyl, arylalkyl, heteroarylalkyl,heteroarylalkylthioalkyl, heteroarylthioalkyl, arylthioalkyl,alkylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, alkenyl, —(CH₂)₁-A[1 is an integer of any of 1 to 4 and A is a nitrogen-containing 5- or6-membered hetero ring, which (a) is bonded via a nitrogen atom, (b) maycontain, as a further hetero atom, at least one kind of atom selectedfrom nitrogen, oxygen and sulfur at a position not adjacent to thebonded nitrogen atom, (c) contains carbon atoms adjacent to the bondednitrogen atom, one or both of which is(are) substituted by oxo, andwhich (d) is benzocondensed or has one or more other carbon atomsoptionally substituted by lower alkyl or oxo, and/or has other nitrogenatom optionally substituted by lower alkyl or phenyl] or —COOR¹⁴ (R¹⁴ ishydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl), or CH₂ when

is a double bond;

[0067] R² is hydrogen, alkyl, arylalkyl, heteroarylalkyl, cycloalkyl,cycloalkylalkyl or aryl;

[0068] Y is O, NR⁷ (R⁷ is as defined for R²) or S;

[0069] n is an integer of any of 1 to 6;

[0070] R³ is hydrogen, halogen (fluorine, chlorine, bromine, iodine),hydroxyl group, trifluoromethyl, cyano, nitro, amino, alkyl, alkoxy,acyloxy, carbamoyl, lower alkylamino or dilower alkylamino group; and

[0071] R⁴ is OR⁸ (R⁸ is hydrogen, lower alkyl, aryl, heteroaryl,arylalkyl or heteroarylalkyl) or NR¹⁰ R¹¹ [R¹⁰ and R¹¹ are the same ordifferent and each is hydrogen, lower alkyl, arylalkyl, heteroaryl,heteroarylalkyl or aryl, or R¹⁰ and R¹¹ may form an optionallysubstituted hetero ring together with the adjacent nitrogen atom];

[0072] or a pharmacologically acceptable salt thereof,

[0073] (11) a compound of the formula (IV)

[0074] wherein

[0075] R⁹ is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl;

[0076]

is a single bond or double bond;

[0077] R¹³ is, when

is a single bond, hydrogen, alkyl, arylalkyl, heteroarylalkyl,heteroarylalkylthioalkyl, heteroarylthioalkyl, arylthioalkyl,alkylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, alkenyl, —(CH₂)₁-A[1 is an integer of any of 1 to 4 and A is a nitrogen-containing 5- or6-membered hetero ring, which (a) is bonded via a nitrogen atom, (b) maycontain, as a further hetero atom, at least one kind of atom selectedfrom nitrogen, oxygen and sulfur at a position not adjacent to thebonded nitrogen atom, (c) contains carbon atoms adjacent to the bondednitrogen atom, one or both of which is(are) substituted by oxo, andwhich (d) is benzocondensed or has one or more other carbon atomsoptionally substituted by lower alkyl or oxo, and/or has other nitrogenatom optionally substituted by lower alkyl or phenyl] or —COOR¹⁴ (R¹⁴ ishydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl), or CH₂ when

is a double bond;

[0078] R² is hydrogen, alkyl, arylalkyl, heteroarylalkyl, cycloalkyl,cycloalkylalkyl or aryl;

[0079] R¹² is a characteristic group of natural or non-natural_(α)-amino acid, wherein a functional group present therein may beprotected;

[0080] R⁶ is hydrogen, lower alkyl, aryl, heteroaryl, arylalkyl orheteroarylalkyl;

[0081] Z is alkylene having 1 to 6 carbon atoms, phenylene ornaphthalene;

[0082] or a pharmacologically acceptable salt thereof,

[0083] (12) a pharmaceutical composition containing the sulfonic acidderivative of hydroxamic acid of any of the above-mentioned (1)-(9) or apharmacologically acceptable salt thereof and a pharmacologicallyacceptable carrier, and

[0084] (13) an LPS inhibitor containing the sulfonic acid derivative ofhydroxamic acid of any of the above-mentioned (1)-(9) or apharmacologically acceptable salt thereof as an active ingredient.

BEST MODE FOR EMBODYING THE INVENTION

[0085] The symbols used in the present specification are explained inthe following.

[0086] The “alkyl” for R¹, R², R³, R⁷, R⁹, R¹³ and R¹⁴ is linear orbranched alkyl having 1 to 10 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, n-hexyl, n-octyl, n-decyl and the like.

[0087] The “lower alkyl” for R³, R⁶, R⁸, R¹⁰ and R¹¹ is linear orbranched alkyl having 1 to 6 carbon atoms, such as methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl,isopentyl, n-hexyl and the like.

[0088] The “aryl” for R², R⁶, R⁷, R⁸, R⁹, R¹⁰, R¹¹ and R¹⁴ is arylhaving 6 to 10 carbon atoms, such as phenyl, naphthyl, aryl which is anortho-fused bicyclic group having 8 to 10 ring atoms wherein at leastone ring is an aromatic ring (e.g., indenyl and the like), and the like,with preference given to phenyl.

[0089] The “heteroaryl” for R⁶, R⁸, R¹⁰ and R¹¹ is a 5- or 6-memberedring group having a carbon atom and 1 to 4 hetero atoms (oxygen, sulfuror nitrogen), ortho-fused bicyclic heteroaryl having 8 to 10 ring atoms,which is derived therefrom, particularly a benzo derivative condensedwith benzene ring, one derived by fusing propenylene, trimethylene ortetramethylene group therewith, stable N-oxide thereof and the like.Examples thereof include pyrrolyl, pyrrolynyl, furyl, thienyl, oxazolyl,isoxazolyl, imidazolyl, thiazolyl, isothiazolyl, pyrazolyl,1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, 1,3,4-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl,pyranyl, pyrazinyl, pyrimidinyl, pyridazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, 1,3,5-triazinyl, 1,2,5-oxathiazinyl,1,2,6-oxathiazinyl, benzoxazolyl, benzothiazolyl, benzoimidazolyl,thianaphtenyl, isothianaphtenyl, benzofuranyl, benzothienyl,isobenzofuranyl, chlomenyl, isoindolyl, indolyl, indazolynyl,isoquinolyl, quinolyl, phthalazinyl, quinoxalynyl, quinazolynyl,synnolynyl, benzoxazinyl and the like, with preference given to pyridyl.

[0090] The “cycloalkyl” for R² is cycloalkyl having 3 to 7 carbon atoms,such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyland the like.

[0091] The cycloalkyl moiety of “cycloalkylalkyl” for R² is as definedfor the above-mentioned “cycloalkyl”, and the alkyl moiety is as definedfor the above-mentioned “lower alkyl”. Examples of such cycloalkylalkylinclude cyclopropylmethyl, 2-cyclobutylethyl, cyclopentylmethyl,3-cyclopentylpropyl, cyclohexylmethyl, 2-cyclohexylethyl,cycloheptylmethyl and the like.

[0092] The “alkenyl” for R¹ and R¹³ is alkenyl having 2 to 6 carbonatoms, such as vinyl, allyl, 3-butenyl, 5-hexenyl and the like.

[0093] The aryl moiety of “arylalkyl” for R¹, R², R⁶, R⁷, R⁸, R⁹, R¹⁰,R¹¹, R¹³ and R¹⁴ is as defined for the above-mentioned “aryl”, and thealkyl moiety is as defined for the above-mentioned “lower alkyl”.Examples of such arylalkyl include benzyl, phenethyl, 3-phenylpropyl,1-naphthylmethyl, 2-naphthylmethyl, 2-(1-naphthyl)ethyl,2-(2-naphthyl)ethyl, 3-(1-naphthyl)propyl, 3-(2-naphthyl)propyl and thelike.

[0094] The heteroaryl moiety of “heteroarylalkyl” for R¹, R², R⁶, R⁷,R⁸, R⁹, R¹⁰, R¹¹, R¹³ and R¹⁴ is as defined for the above-mentioned“heteroaryl”, and the alkyl moiety is as defined for the above-mentioned“lower alkyl”. Examples of such heteroarylalkyl include2-pyrrolylmethyl, 2-pyridylmethyl, 3-pyridylmethyl, 4-pyridylmethyl,2-thienylmethyl, 2-(2-pyridyl)ethyl, 2-(3-pyridyl)ethyl,2-(4-pyridyl)ethyl, 3-(2-pyrrolyl)propyl and the like.

[0095] The alkyl moiety of the alkylthio moiety of “alkylthioalkyl” forR¹ and R¹³ is as defined for the above-mentioned “alkyl”, and theremaining alkyl moiety is as defined for the above-mentioned “loweralkyl”. Examples of such alkylthioalkyl include methylthiomethyl,ethylthiomethyl, n-propylthiomethyl, isopropylthiomethyl,n-butylthiomethyl, isobutylthiomethyl, sec-butylthiomethyl,tert-butylthiomethyl and the like.

[0096] The aryl moiety of “arylthioalkyl” for R¹ and R¹³ is as definedfor the above-mentioned “aryl”, and the alkyl moiety is as defined forthe above-mentioned “lower alkyl”. Examples of such arylthioalkylinclude phenylthiomethyl, 1-naphthylthiomethyl, 2-naphthylthiomethyl andthe like.

[0097] The heteroaryl moiety of “heteroarylthioalkyl” for R¹ and R¹³ isas defined for the above-mentioned “heteroaryl”, and the alkyl moiety isas defined for the above-mentioned “lower alkyl”. Examples of suchheteroarylthioalkyl include 2-pyrrolylthiomethyl, 2-pyridylthiomethyl,3-pyridylthiomethyl, 4-pyridylthiomethyl, 2-thienylthiomethyl and thelike.

[0098] The arylalkyl moiety of “arylalkylthioalkyl” for R¹ and R¹³ is asdefined for the above-mentioned “arylalkyl”, and the remaining alkylmoiety is as defined for the above-mentioned “lower alkyl”. Examples ofsuch arylalkylthioalkyl include benzylthiomethyl, phenethylthiomethyland the like.

[0099] The heteroarylalkyl moiety of “heteroarylalkylthioalkyl” for R¹and R¹³ is as defined for the above-mentioned “heteroarylalkyl”, and theremaining alkyl moiety is as defined for the above-mentioned “loweralkyl”. Examples of such heteroarylalkylthioalkyl include2-pyrrolylmethylthiomethyl, 2-pyridylmethylthiomethyl,3-pyridylmethylthiomethyl, 4-pyridylmethylthiomethyl,2-thienylmethylthiomethyl and the like.

[0100] The alkyl moiety of “phthalimidoalkyl” for R¹ and R¹³ is asdefined for the above-mentioned “lower alkyl”. Examples of suchphthalimidoalkyl include phthalimidomethyl, 2-phthalimidoethyl and thelike.

[0101] The A of —(CH₂)₁-A for R¹ and R¹³ is a nitrogen-containing heteroring bonded via a nitrogen atom and is exemplified by the followinggroups.

[0102] wherein

[0103]

is a single bond when R′ and R″ are each hydrogen and a double bond whenR′ and R″ in combination form a ring,

[0104] R′″ is hydrogen, lower alkyl or phenyl,

[0105] Q′ is —CO—, —CH₂—, —CH(lower alkyl)—, —C(lower alkyl)₂—, —NH—,—N(lower alkyl)— or —O—, and

[0106] T′ is —O—, —NH— or —N(lower alkyl)—.

[0107] The preferable nitrogen-containing hetero ring is exemplified by2-oxo-1-pyrrolizinyl, 2,5-dioxo-1-pyrrolizinyl,1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl,3-methyl-2,5-dioxo-1-imidazolidinyl,3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl,2-methyl-3,5-dioxo-1,2,4-oxadiazolidin-4-yl,3-methyl-2,4,5-trioxo-1-imidazolidinyl,2,5-dioxo-3-phenyl-1-imidazolidinyl and 2,6-dioxopiperidino and thelike, the rings of the formulas (ii) and (iii), particularly preferably1,2-dimethyl-3,5-dioxo-1,2,4-triazolidin-4-yl,3-methyl-2,5-dioxo-1-imidazolidinyl and3,4,4-trimethyl-2,5-dioxo-1-imidazolidinyl.

[0108] The aforementioned arylalkyl, heteroarylalkyl,heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl,heteroarylalkylthioalkyl, phthalimidoalkyl, aryl and heteroaryl areoptionally substituted by one or more substituents selected from halogen(fluorine, chlorine, bromine, iodine), hydroxyl group, nitro, cyano,trifluoromethyl, lower alkyl (provided that it does not substitute thealkyl moiety of arylalkyl, heteroarylalkyl, heteroarylthioalkyl,arylthioalkyl, arylalkylthioalkyl and phthalimidoalkyl), alkoxy,alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl, carboxyl, a grouprepresented by —COOR_(a) [R_(a) is lower alkyl, arylalkyl or aryl],carbamoyl, amino, lower alkylamino, dilower alkylamino, guanidino,hydroxysulfonyloxy, arylalkyloxyalkyl and the like. As used herein,“lower alkyl”, “arylalkyl” and “aryl” are as mentioned above.

[0109] The “alkoxy” is linear or branched alkoxy having 1 to 6 carbonatoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy,tert-butoxy and the like.

[0110] The alkyl moiety of “alkylthio” is as defined for theabove-mentioned “lower alkyl”. Examples of such alkylthio includemethylthio, ethylthio, n-propylthio, isopropylthio and the like.

[0111] The “acyloxy” is linear or branched alkanoyloxy having 2 to 6carbon atoms, such as acetyloxy, propionyloxy, butyryloxy, valeryloxy,pivaloyloxy, hexanoyloxy and the like.

[0112] The arylalkyl moiety of “arylalkyloxyalkyl” is as defined for theabove-mentioned “arylalkyl”, and the remaining alkyl moiety is asdefined for the above-mentioned “lower alkyl”. Examples of sucharylalkyloxyalkyl include benzyloxymethyl, phenethyloxymethyl and thelike.

[0113] The “optionally substituted hetero ring” formed by R¹⁰ and R¹¹together with the adjacent nitrogen atom is a 4- to 7-membered ringgroup having carbon atom(s) and at least one nitrogen atom, andoptionally having, as a further hetero atom in the ring, at least onekind of atom selected from nitrogen, oxygen and sulfur, wherein thecarbon atom(s) constituting the ring may be substituted by oxo, andfurthermore, an aromatic ring such as benzene ring and the like may becondensed utilizing adjacent two carbon atoms constituting the heteroring. Examples of such hetero ring include azetidino, 1-pyrrolizinyl,piperidino, 1-piperazinyl, morpholino, thiomorpholino,oxothiomorpholino, dioxothiomorpholino, 2-oxo-1-quinazolynyl and thelike.

[0114] When the hetero ring contains a nitrogen atom as a further heteroatom in the ring, as in 1-piperazinyl, lower alkyl (as mentioned above),arylalkyl (as mentioned above), heteroarylalkyl (as mentioned above),aryl (as mentioned above), heteroaryl (as mentioned above), a grouprepresented by —COOR_(a) (R_(a) is as mentioned above) or acyl may besubstituted on the nitrogen atom. Here, acyl is a group represented by—COR_(a), wherein R_(a) is as mentioned above.

[0115] The characteristic group of the natural or non-natural _(α)-aminoacid for R¹² is a group R in the natural or non-natural _(α)-amino acidrepresented by H₂N—CH(R)—COOH. Examples of the characteristic groupderived from the natural _(α)-amino acid are as follows, wherein thecorresponding amino acids are shown in the parentheses: hydrogen(glycine), methyl (alanine), isopropyl (valine), isobutyl (leucine),benzyl (phenylalanine), p-hydroxybenzyl (tyrosine), hydroxymethyl(serine), mercaptomethyl (cysteine), 1-hydroxyethyl (threonine),2-methylthioethyl (methionine), carboxymethyl (aspartic acid),2-carboxyethyl (glutamic acid), 2-indolylmethyl (tryptophan),4-imidazolylmethyl (histidine), 4-aminobutyl (lysin) and3-guanidinopropyl (arginine). Examples of the characteristic groupderived from the non-natural _(α)-amino acid are as follows, wherein thecorresponding non-natural amino acids are shown in the parentheses:ethyl (_(α)-amino-n-butyric acid), n-propyl (_(α)-amino-n-pentanoicacid), n-butyl (_(α)-amino-n-heptanoic acid), n-heptyl(_(α)-amino-n-nonanoic acid), cyclohexylmethyl (cyclohexylalanine),phenyl (_(α)-amino-phenylacetic acid), 2-phenylethyl(homophenylalanine), 1-naphthyl (_(α)-amino-1-naphthylacetic acid),2-naphthyl (_(α)-amino-2-naphthylacetic acid), phenethyl(_(α)-amino-3-phenylbutanoic acid), _(α)-methylbenzyl(_(β)-methylphenylalanine), _(α),_(α)-dimethylbenzyl(_(β),_(β)-dimethylphenylalanine) and the like.

[0116] The optional (reactive) functional group present in R¹² can beprotected by a method known in peptide chemistry. For example, aminogroup can be protected in the form of tert-butoxycarbonyl,benzyloxycarbonyl or isobornyloxycarbonyl group, or phthalimido group.The carboxyl group can be protected in the form of methyl, ethyl,tert-butyl, benzyl and the like. The hydroxy group can be protected inthe form of tert-butyl, benzyl or tetrahydropyranylether, or in the formof acetate. The mercapto group can be protected in the form oftert-butyl, benzyl, or by a similar group.

[0117] The “hydroxyl-protecting group” for X is, for example, arylalkyl,aryl, heteroaryl, silyl (e.g., trimethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl and the like), 2-tetrahydropyranyl and the like.The arylalkyl, aryl and heteroaryl optionally have one or moresubstituents selected from, for example, halogen (fluorine, chlorine,bromine, iodine), hydroxyl group, nitro, cyano, trifluoromethyl, loweralkyl (provided that it does not substitute the alkyl moiety ofarylalkyl), alkoxy, alkylthio, formyl, acyloxy, oxo, phenyl, arylalkyl,carboxyl, a group represented by —COOR_(a) [R_(a) is lower alkyl,arylalkyl or aryl], carbamoyl, amino, lower alkylamino, diloweralkylamino, guanidino, hydroxysulfonyloxy, arylalkyloxyalkyl and thelike. The protecting group of hydroxyl group of the compound of thepresent invention is preferably silyl, 2-tetrahydropyranyl, benzyl andthe like.

[0118] The “alkylene” for Z is a methylene chain having 1 to 5 carbonatoms, such as methylene, ethylene, propylene, butylene or pentylene andthe like.

[0119] The “phenylene” for Z is a divalent aromatic hydrocarbon grouprepresented by —C₆H₄—, such as 1,2-, 1,3- or 1,4-phenylene.

[0120] The “naphthalene” for Z is a divalent aromatic hydrocarbon grouprepresented by —C₁₀H₆—, such as 1,2-, 1,4-, 1,5-, 2,5- or2,8-naphthalene and the like.

[0121] The phenylene and naphthalene for the aforementioned Z areoptionally substituted by one or more substituents selected from halogen(fluorine, chlorine, bromine, iodine), hydroxyl group, nitro, cyano,trifluoromethyl, lower alkyl, alkoxy, acyloxy, hydroxysulfonyl,hydroxysulfonyloxy and the like. As used herein, “lower alkyl”, “alkoxy”and “acyloxy” are as mentioned above.

[0122] When the sulfonic acid derivatives of hydroxamic acid representedby the formulas (I) and (II), compounds represented by the formulas(III) and (IV) and pharmacologically acceptable salts thereof have anasymmetric carbon, they can be present as an optically active form or aracemate. The racemate can be separated into each optically active formby a means known per se. When the sulfonic acid derivative of hydroxamicacid and a pharmacologically acceptable salt thereof have an additionalasymmetric carbon, the compound can be present as a diastereomermixture, or as a single diastereomer, which can be also separated by ameans known per se.

[0123] The sulfonic acid derivative of hydroxamic acid and apharmacologically acceptable salt thereof can show polymorphism, and canbe present as more than one tautomers, and further, can be present as asolvate.

[0124] Accordingly, the present invention encompasses the aforementionedany stereoisomer, optical isomer, polymorph, tautomer, solvate, optionalmixtures thereof and the like. Optically active form, racemate anddiastereomer are also encompassed in the scope of the present invention.

[0125] The pharmacologically acceptable salts of the sulfonic acidderivatives of hydroxamic acid represented by the formulas (I) and (II)and the compounds of the formulas (III) and (IV) may be, for example,alkali metal salt (salt with lithium, sodium, potassium and the like),alkaline earth metal salt (salt with calcium, magnesium and the like),aluminum salt, ammonium salt, salt with organic base (triethylamine,morpholine, piperidine, triethanolamine, trishydroxymethylaminomethane,meglumine and the like), salt with natural _(α)-amino acid (alanine,phenylalanine, histidine, lysin, arginine and the like), and the like.

[0126] Other pharmacologically acceptable salts may be, for example,inorganic acid addition salt (salt with hydrochloric acid, hydrobromicacid, hydroiodic acid, sulfuric acid, phosphoric acid and the like),organic acid addition salt (salt with methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, formic acid, acetic acid,trifluoroacetic acid, oxalic acid, citric acid, malonic acid, fumaricacid, glutaric acid, adipic acid, maleic acid, tartaric acid, succinicacid, mandelic acid, malic acid and the like), salt with amino acid(glutamic acid, aspartic acid and the like) and the like. Moreover, asalt may be formed with oxalic acid for crystallization.

[0127] Preferable embodiment of the sulfonic acid derivatives ofhydroxamic acid represented by the formulas (I) and (II), and compoundsrepresented by the formulas (III) and (IV) is exemplified by a free acidor pharmacologically acceptable salt. Crystallization is possible inboth forms, and an optional derivative and an isomer thereof can beprepared at high purity in a large amount.

[0128] Preferable embodiments of the sulfonic acid derivatives ofhydroxamic acid represented by the formulas (I) and (II), andpharmacologically acceptable salts thereof are exemplified by a sulfonicacid derivative of hydroxamic acid of the formula (I) or (II), whereinR¹ is phthalimidomethyl, or a pharmacologically acceptable salt thereof,a sulfonic acid derivative of hydroxamic acid of the formula (I) or(II), wherein R² is isobutyl, or a pharmacologically acceptable saltthereof, a hydroxamic acid derivative, wherein, in the formula (I), R³is hydrogen, or a pharmacologically acceptable salt thereof, ahydroxamic acid derivative of the formula (I), wherein R⁴ is NHCH₃ orNHC₆H₅, or a pharmacologically acceptable salt thereof, a sulfonic acidderivative of hydroxamic acid of the formula (II), wherein R¹² isbenzyl, or a pharmacologically acceptable salt thereof, a sulfonic acidderivative of hydroxamic acid of the formula (II), wherein R⁶ ishydrogen, or a pharmacologically acceptable salt thereof, and the like.

[0129] Specifically, the compounds of Examples 1, 2, 10, 11, 13, 14, 15,17, 19, 21 and 22 in the Examples below are preferable compounds,including these preferable embodiments.

[0130] The preparation methods of the sulfonic acid derivative ofhydroxamic acid or a pharmacologically acceptable salt thereof of thepresent invention are shown in the following.

[0131] Preparation Methods of Sulfonic Acid Derivative of HydroxamicAcid which is Represented by of the Formula (I)

[0132] wherein n is an integer of 1 to 6, R^(9′) is as defined for R⁹(except hydrogen) and R¹, R², R³, R⁴, X and Y are as defined above.

[0133] As shown in the above-mentioned Scheme 1, the sulfonic acidderivative of hydroxamic acid (I) or a pharmacologically acceptable saltthereof of the present invention can be prepared by convertingcarboxylic acid (VII) as a starting material using an amino derivative(VIII) according to the C terminus activation method for peptidesynthesis [e.g., Pepuchidogousei no kiso to jikken, Izumiya et al.,Maruzen Shoten, p 91] to an intermediate compound (VIa), and viaconversion of this compound to sulfonic acid derivative (Va) andsulfonic acid derivative (IIIa). The carboxylic acid (VII) to be thestarting material is a compound described in a reference (JapanesePatent Application under PCT laid-open under kohyo No. H6-506445,JP-A-4-352757, JP-A-7-157470, Japanese Patent Application under PCTlaid-open under kohyo No. H4-502008, JP-A-6-65196, specification ofWO96/33968, specification of WO94/21625 and the like), or preparedaccording to a conventional method based on these references.

[0134] The amino derivative (VIII) can be prepared by, for example, themethod to be explained below.

[0135] The detail of each step is explained in the following.

[0136] Step 1

[0137] In Step 1, carboxylic acid (VII) and amino derivative (VIII) arereacted to give intermediate compound (VIa).

[0138] The representative method is shown in the following.

[0139] Step 1-1) Method Using Mixed Acid Anhydride

[0140] The intermediate compound (VIa) can be obtained by reactingcarboxylic acid (VII) with isobutyl chlorocarbonate in the presence ofan amine base such as triethylamine, N-methylmorpholine and the like,and reacting the resultant compound with amino derivative (VIII). Thesolvent used may be an aprotic solvent such as tetrahydrofuran (THF),methylene chloride, ethyl acetate, N,N-dimethylformamide (DMF) and thelike, and the reactions can be carried out at −15° C. to roomtemperature.

[0141] Step 1-2) Method Using Acid Chloride

[0142] Carboxylic acid (VII) is reacted with oxalyl chloride or thionylchloride to once give an acid chloride. The solvent used is methylenechloride or a hydrocarbon solvent such as benzene, toluene and the like,and the reaction is carried out at −15° C. to room temperature or underheating. The intermediate compound (VIa) can be obtained by reacting theobtained acid chloride with amino derivative (VIII) in the presence ofan amine base such as triethylamine, pyridine and the like. The solventused is an aprotic solvent such as THF, ethyl acetate, DMF, methylenechloride, benzene, toluene and the like, and the reaction can be carriedout at −15° C. to room temperature or under heating.

[0143] Step 1-3) Method Using DCC-HOBt Method (Coupling Method)

[0144] The intermediate compound (VIa) can be obtained by reactingcarboxylic acid (VII) and amino derivative (VIII) with1,3-dicyclohexylcarbodiimide (DCC) and 1-hydroxybenzotriazole (HOBt) or3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (HOOBt) as acondensation agent, in the presence of an amine base such astriethylamine or N-methylmorpholine and the like, at a temperature ofnot higher than room temperature. As the condensation agent,1,3-diisopropylcarbodiimide (DIPCI),1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSCI.HCl)or benzotriazol-1-yl-oxy-tris-(dimethylamino)-phosphoniumhexafluorophosphate (BOP reagent) and the like can be used instead ofDCC. The solvent used is an aprotic solvent such as THF, methylenechloride, ethyl acetate, DMF, pyridine and the like.

[0145] Step 1-4) Method Using Active Ester Method

[0146] Carboxylic acid (VII) and a phenol derivative such aspentafluorophenol and the like or N-hydroxysuccinimide are reacted witha condensation agent such as DCC and the like to once give an activeester. An amine base is used as necessary, and the amine base to be usedis triethylamine or N-methylmorpholine and the like. The solvent used isan aprotic solvent such as THF, DMF, methylene chloride and the like,and the reaction is carried out at a temperature not higher than roomtemperature. The intermediate compound (VIa) can be obtained by reactingthe obtained active ester with amino derivative (VIII). An amine base isused as necessary, and the amine base to be used is triethylamine orN-methylmorpholine and the like. The solvent used is an aprotic solventsuch as THF, DMF, methylene chloride and the like, and the reaction canbe carried out at a temperature not higher than room temperature.

[0147] Step 2

[0148] The sulfonic acid derivative (Va) can be obtained by reactingintermediate compound (VIa) with haloalkanesulfonic acid or sultone inthe presence of an inorganic base such as potassium carbonate or cesiumcarbonate and the like. The solvent used is an aprotic solvent such asDMF, acetonitrile, acetone and the like, and the reaction can be carriedout at −15° C. to room temperature or under heating.

[0149] Step 3

[0150] In Step 3, sulfonic acid derivative (Va) is converted to sulfonicacid derivative (IIIa). For example, when R^(9′) can be removed with anacid, such as a tert-butyl group, sulfonic acid derivative (Va) can beconverted to sulfonic acid derivative (IIIa) by reacting with hydrogenchloride or trifluoroacetic acid. The solvent used is an ether solventsuch as 1,4-dioxane and the like, or methylene chloride and the like,and the reaction can be carried out at a temperature of not higher thanroom temperature.

[0151] Step 4

[0152] In Step 4, sulfonic acid derivative (IIIa) is reacted withunprotected hydroxylamine (XONH₂; X is as defined above or hydroxylamineprotected by silyl (trimethylsilyl, tert-butyldimethylsilyl,tert-butyldiphenylsilyl and the like), tert-butyl, benzyl,benzyloxymethyl, p-methoxybenzyl, 2-nitrobenzyl, 2-tetrahydropyranyl(Chem. Pharm. Bull. Jpn. 23, 167, 1975) group and the like) forconversion thereof to sulfonic acid derivative of hydroxamic acid (I).As the reaction conditions, those of Step 1 can be applied. Whenprotected hydroxylamine is used, the protecting group can be removedafter reaction under general deprotection conditions of hydroxyl group[T. W. Greene et. al., PROTECTIVE GROUPS IN ORGANIC SYNTHESIS, 2^(nd)ed., (JOHN WILEY & SONS, Inc.)].

[0153] The sulfonic acid derivative (Va) can be also prepared by amethod shown in the following Scheme 2.

[0154] wherein n is an integer of 1 to 6, and R¹, R², R³, R⁴, R^(9′) andY are as defined above.

[0155] Step 5

[0156] In Step 5, carboxylic acid (VII) and amino derivative (IX) arereacted to give sulfonic acid derivative (Va). This step can beconducted by the same method as in Step 1.

[0157] The sulfonic acid derivative of hydroxamic acid (I) of thepresent invention can be also prepared by the method shown in thefollowing Scheme 3.

[0158] wherein n is an integer of 1 to 6, X′ and W are the same ordifferent and as defined for X, and R¹, R², R³, R⁴, X and Y are asdefined above.

[0159] Step 6

[0160] In Step 6, carboxylic acid (X) and amino derivative (IX) arereacted to give sulfonic acid derivative (Ia). This step can be carriedout by the same method as in Step 1.

[0161] Step 7

[0162] In Step 7, sulfonic acid derivative (Ia) is converted to sulfonicacid derivative of hydroxamic acid (I), and can be carried out by thesame method as in Step 4, whether or not W is the same as or differentfrom X.

[0163] The carboxylic acid (X) can be prepared by, for example, themethod explained in Scheme 6 below. The amino derivatives (VIII) and(IX) can be prepared by, for example, the method to be explained inScheme 5 below.

[0164] The desired substituent R¹ can be introduced by the method shownin the aforementioned Schemes 1-3 and without a special step, by the useof carboxylic acid (VII) or (X) having the substituent. In addition, forexample, the method shown in the following Scheme 4 can be also used.

[0165] wherein n is an integer of 1 to 6, R¹ is heteroarylthioalkyl,arylthioalkyl, heteroarylalkylthioalkyl of arylalkylthioalkyl, R^(14′)is as defined for R¹⁴ (except hydrogen), and R², R³, R⁴, R^(9′) and Yare as defined above.

[0166] Step 8

[0167] In Step 8, carboxylic acid (XI) and amino derivative (VIII) arereacted to give intermediate compound (VIb). This step can be conductedby the same method as in Step 1. The carboxylic acid (XI) to be thestarting material is described in references (JP-A-7-157470 and thelike), or prepared by a conventional method based on these references.

[0168] Step 9

[0169] In Step 9, intermediate compound (VIb) and haloalkanesulfonicacid or sultone are reacted to give sulfonic acid derivative (Vb). Thisstep can be conducted by the same method as in Step 2.

[0170] Step 10

[0171] In Step 10, carboxylic acid (XI) and amino derivative (IX) arereacted to give sulfonic acid derivative (Vb). This step can beconducted by the same method as in Step 1.

[0172] Step 11

[0173] In Step 11, the substituents R^(9′) and R^(14′) of sulfonic acidderivative (Vb) are removed to give sulfonic acid derivative (IIIb). Forexample, when R^(9′) and R^(14′) are benzyl groups, a general catalytichydrogenation reaction is carried out in the presence of a metalcatalyst at normal pressure or under pressurization. As the metalcatalyst, palladium on carbon, palladium black and the like can be used,the solvent used is an ether solvent such as 1,4-dioxane and the like,an ester solvent such as ethyl acetate and the like or an alcoholsolvent such as methanol, ethanol, isopropyl alcohol and the like, andthe reaction can be carried out at room temperature or under heating.

[0174] Step 12

[0175] In Step 12, sulfonic acid derivative (IIIb) obtained in Step 11is subjected to decarboxylation for conversion thereof to sulfonic acidderivative (IIIc). The solvent used is a hydrocarbon solvent such asn-hexane, benzene, toluene and the like, and where necessary, thereaction can be carried out in the presence of a tertiary amine, such asN-methylmorpholine, triethylamine and the like, at room temperature orunder heating.

[0176] Step 13

[0177] In Step 13, sulfonic acid derivative (IIIb) obtained in Step 11is reacted with formaldehyde in the presence of a secondary amine forconversion thereof to sulfonic acid derivative (IIId). As the secondaryamine, piperidine, diethylamine, morpholine and the like are used andthe reaction can be carried out in an alcohol solvent such as methanol,ethanol and the like or an amide solvent such as DMF and the like atroom temperature or under heating.

[0178] Step 14

[0179] In Step 14, sulfonic acid derivative (IIId) obtained in Step 13is reacted with arylthiol, heteroarylthiol, alkylthiol,heteroarylalkylthiol or arylalkylthiol as a nucleophile to give sulfonicacid derivative (IIIa), wherein the substituent R¹ is arylthioalkyl,heteroarylthioalkyl, alkylthioalkyl, heteroarylalkylthioalkyl orarylalkylthioalkyl. This reaction can be carried out without solvent orin a halogenated hydrocarbon solvent such as methylene chloride and thelike, an alcohol solvent such as methanol and the like or an amidesolvent such as DMF and the like at room temperature or under heating.

[0180] The amino derivatives (VIII) and (IX) which are startingcompounds in Scheme 1-4 can be prepared by the method shown in thefollowing Scheme 5.

[0181] wherein n is an integer of 1 to 6, A′ is an amino-protectinggroup such as tert-butoxycarbonyl, benzyloxycarbonyl and the like, L isalkoxy, hydroxyl group, halogen atom such as chlorine, bromine, iodineand the like that can be derived therefrom or sulfonic acid ester suchas methanesulfonyloxy, p-toluenesulfonyloxy, trifluoromethanesulfonyloxyand the like, and R³, R⁴ and Y are as defined above.

[0182] Step 15

[0183] In Step 15, compound (XIIa) and various amines or alcohol arereacted to give compound (XIIb). This step can be conducted by the samemethod as in Step 1.

[0184] Step 16

[0185] In Step 16, the amino-protecting group of compound (XIIb) isremoved to give amino derivative (VIII).

[0186] When the protecting group A′ is tert-butoxycarbonyl group, it canbe removed under acidic conditions using trifluoroacetic acid, hydrogenchloride-containing dioxane, hydrogen chloride-containing methanol,hydrogen bromide-containing acetic acid and the like. The inert solventto be used is preferably a halogenated hydrocarbon solvent such asmethylene chloride, chloroform and the like, an ether solvent such asdiethyl ether, THF, dioxane and the like, an alcohol solvent such asmethanol, ethanol, n-propyl alcohol, isopropyl alcohol and the like, oran organic acid such as acetic acid and the like.

[0187] The reaction temperature is generally 0-100° C., preferably 0-50°C. The reaction time is generally 15 min-12 hr, preferably 15 min-4 hr.

[0188] When the protecting group A′ is benzyloxycarbonyl group, a methodfor removing by a treatment with an acid or a method for removing bycatalytic reduction is preferable.

[0189] The acid to be used for the method using an acid is preferablytrifluoromethanesulfonic acid. The solvent to be used is preferablymethylene chloride. The reaction temperature and the reaction time arepreferably 0-50° C. and 5 min-6 hr.

[0190] The catalyst to be used for the method based on catalyticreduction is preferably palladium on carbon or palladium black. Thesolvent to be used is preferably an alcohol solvent such as methanol,ethanol, n-propyl alcohol, isopropyl alcohol and the like, an ethersolvent such as diethyl ether, tetrahydrofuran, 1,4-dioxane and thelike, an ester solvent such as ethyl acetate and the like. The pressureof hydrogen in this method is generally 1-10 atm, and the reactiontemperature and the reaction time are preferably 0-100° C. and 5 min-24hr.

[0191] Step 17

[0192] In Step 17, compound (XIIb) and haloalkanesulfonic acid orsultone are reacted to give compound (XIIc). This step can be conductedby the same method as in Step 2.

[0193] Step 18

[0194] In Step 18, the amino-protecting group of compound (XIIc) isremoved to give amino derivative (IX), and can be conducted by the samemethod as in Step 16.

[0195] Step 19

[0196] In Step 19, compound (XIIb) is alkylated for conversion thereofto a compound (XIId: L=leaving group) having a leaving group in theterminal, by a single step or stepwisely, which can be conducted by thesame method as in method 1) or 2) shown in the following.

[0197] Step 19-1) Single Step Synthetic Method

[0198] The compound (XIIb) is reacted with an alkylating agent forconversion thereof to a compound (XIId: L=halogen), and can be conductedby the same method as in Step 2. As the alkylating agent, alkyl dihalidehaving a desired carbon chain, such as dibromomethane,1,2-dibromoethane, 1-chloro-3-bromopropane, 1-chloro-4-bromobutane,1-chloro-5-bromopentane and the like can be used.

[0199] Step 19-2) Stepwise Synthetic Method

[0200] This method consists of the following three steps i) to iii).

[0201] i) A step for converting compound (XIIb) to a compound (XIId:L=alkoxy) by reacting with mono-protected diol having a desired carbonchain length by Mitsunobu reaction [J. Med. Chem., 1994, 37, 674] forconversion thereof. As the mono-protected diol, 2-benzyloxyethanol,2-t-butyldimethylsiloxyethanol, 3-benzyloxypropanol, 4-benzyloxybutanol,5-benzyloxypentanol and the like can be used. As the activating reagent,triphenylphosphine and diethylazodicarboxylate (DEAD) are preferable.The solvent used is an aprotic solvent such as DMF, acetonitrile, THF,dioxane, methylene chloride, chloroform and the like. This step can becarried out at −15° C. to room temperature or under heating.

[0202] ii) A step for converting compound (XIId: L=alkoxy) to compound(XIId: L=hydroxyl group) by deprotection, which can be carried out inthe same manner as in Step 4.

[0203] iii) A step for converting hydroxyl group of compound (XIId:L=hydroxyl group) to a compound (XIId: L=leaving group) having a leavinggroup such as halogen, sulfonic acid ester and the like. When L ishalogen, this step can be carried out by reacting compound (XIId:L=hydroxyl group) with carbon tetrachloride or carbon tetrabromide inthe presence of triphenylphosphine. As the solvent, an aprotic solventsuch as acetonitrile, THF, dioxane, methylene chloride, chloroform andthe like can be used. The reaction temperature of this step ispreferably −15° C. to room temperature or under heating. When L issulfonic acid ester, this step can be carried out by reacting compound(XIId: L=hydroxyl group) with a desired sulfonylating agent in thepresence of an amine base. As the sulfonylating agent, methanesulfonicacid anhydride, trifluoromethanesulfonic acid anhydride andp-toluenesulfonyl chloride are preferable, and as the amine base,triethylamine, pyridine, 2,6-lutidine, 2,4,6-collidine,diisopropylethylamine and the like are preferable. As the solvent, anaprotic solvent such as acetonitrile, THF, dioxane, toluene, methylenechloride, chloroform and the like can be used. The reaction temperatureof this step is preferably −15° C. to room temperature.

[0204] Step 20

[0205] In Step 20, the compound (XIId: L=leaving group) obtained in step19 is converted to compound (XIIc). This step can be carried outaccording to the method described in reference [F. Cortes, OrganicSynthesis, II, 564 (1943)]. As the hydroxysulfonylating agent, sodiumsulfite, sodium hydrogensulfite and the like are preferable. As thesolvent, water or water-containing alcohol can be used. The reactiontemperature of this step is preferably from room temperature or underheating.

[0206] The carboxylic acid (X), which is a starting compound in Scheme3, can be prepared by the method shown in the following Scheme 6.

[0207] wherein X′ and W are as defined for X, R^(9′) and R^(14′) are thesame or may, in combination, take a cyclic structure such as methylenegroup (—CH₂—) or dimethylmethylene [—C(CH₃)₂—], R^(15′) is as definedfor R^(9′) and R^(14′) (provided that R^(15′) is selected from groupsother than R^(9′) and R^(14′)), and R¹, R², R^(9′), R^(14′) and X are asdefined above.

[0208] Step 21

[0209] In Step 21, compound (XIa) is converted to compound (XIb) bydeprotection. For example, when R^(15′) is benzyl group and R^(9′) andR^(14′) are t-butyl groups, a method similar to that in Step 3 can beemployed, and in a reverse case (R^(15′): t-butyl group, R^(9′) andR^(14′): benzyl), the same method as in Step 11 can be employed. Thecompound (XIa) to be the starting material is a compound described inJP-A-7-157470 or a compound prepared by a conventional method based onthis reference.

[0210] Step 22

[0211] In Step 22, compound (XIb) is converted to compound (VIIa) bydecarboxylation, which can be conducted by a method similar to that inStep 12.

[0212] Step 23

[0213] In Step 23, compound (VIIa) is reacted with N,O-disubstitutedhydroxylamine [X′ON(W)H] for conversion thereof to compound (Xa), whichcan be conducted by a method similar to that in Step 1. TheN,O-disubstituted hydroxylamine [X′ON(W)H] can be prepared by aconventional method using O-protected hydroxylamine [X′ONH₂] which iscommercially available or obtained by the method described in areference (Chem. Pharm. Bull. Jpn. 1975, 23, 167).

[0214] Step 24

[0215] In Step 24, compound (Xa) is converted to carboxylic acid (X) bydeprotection, wherein the protecting group can be removed by the methoddescribed in a reference [T. W. Greene et. al., PROTECTIVE GROUPS INORGANIC SYNTHESIS, 2^(nd) ed., (JOHN WILEY & SONS, Inc.)].

[0216] The compound (XIIa), which is a starting compound in Scheme 5,can be prepared by the following method.

[0217] The compound (XIIa) can be prepared by protecting an amino groupof amino acid represented by the formula

[0218] with an amino-protecting group such as tert-butoxycarbonyl group,benzyloxycarbonyl group and the like [e.g., Pepuchidogousei no kiso tojikken, Izumiya et al., Maruzen Shoten, p 16].

[0219] Preparation Method of Sulfonic Acid Derivative of HydroxamicAcid, which is Represented by the Formula (II)

[0220] wherein R^(6′) and R^(6″) are as defined for R⁶ (provided R^(6′)is not hydrogen), X′ is as defined for X, and R¹, R², R⁶, R¹², X and Zare as defined above.

[0221] The sulfonic acid derivative of hydroxamic acid (II) and apharmacologically acceptable salt thereof of the present invention canbe synthesized by the method shown in Scheme 7. First, carboxylic acid(VII) and amino derivative (XVIII) are condensed by the C-terminalactivation method in peptide synthesis [e.g., Pepuchidogousei no kiso tojikken, Izumiya et al., Maruzen Shoten, p 91] to give intermediatecompound (XVII), which is then converted to succinic acid derivative(XVI). Then, it is converted to O-protected hydroxamic acid derivative(XV), and after conversion to intermediate compound (XIV) and then tosulfonic acid derivative of O-protected hydroxamic acid (XIII), the acid(XIII) is deprotected.

[0222] The carboxylic acid (VII) to be the starting material is as theaforementioned, and amino derivative (XVIII) can be prepared by, forexample, the method to be explained in the following Scheme 11.

[0223] The detail of each step is explained in the following.

[0224] Step 25

[0225] In Step 25, carboxylic acid (VII) and amino derivative (XVIII)are reacted to give intermediate compound (XVII), which can be conductedby a method similar to that in Step 1.

[0226] Step 26

[0227] In Step 26, intermediate compound (XVII) is converted to succinicacid derivative (XVI), which can be conducted by a method similar tothat in Step 3.

[0228] Step 27

[0229] In Step 27, succinic acid derivative (XVI) is converted toO-protected hydroxamic acid derivative (XV), which can be conducted by amethod similar to that in Step 4.

[0230] Step 28

[0231] In Step 28, O-protected hydroxamic acid derivative (XV) isconverted to intermediate compound (XIV) by deprotection. When R^(6′) isbenzyl group in this step, a method for deprotection by catalyticreduction is preferable. The catalyst for the method by catalyticreduction is preferably palladium on carbon or palladium black. Thesolvent is preferably an alcohol solvent such as methanol, ethanol,n-propyl alcohol, isopropyl alcohol and the like, an ether solvent suchas diethyl ether, THF, 1,4-dioxane and the like, or an ester solventsuch as ethyl acetate and the like. In this reaction, The pressure ofhydrogen is generally 1-10 atm, and the reaction temperature andreaction time are preferably 0-100° C. and 5 min-24 hr.

[0232] Step 29

[0233] In Step 29, intermediate compound (XIV) is reacted withaminoalkanesulfonic acid derivative: R^(6″)—NH—Z—SO₃H (R^(6″) and Z areas defined above) to give sulfonic acid derivative of O-protectedhydroxamic acid (XIII). This step can be conducted by the same method asin Step 1.

[0234] Step 30

[0235] In Step 30, sulfonic acid derivative of O-protected hydroxamicacid (XIII) is converted to sulfonic acid derivative of hydroxamic acid(II). The protecting group of sulfonic acid derivative of O-protectedhydroxamic acid (XIII) can be removed under generalhydroxyl-deprotection conditions as in Step 4.

[0236] The sulfonic acid derivative of O-protected hydroxamic acid(XIII) can be also prepared by the method shown in the following Scheme8.

[0237] wherein R¹, R², R¹², R^(6″), R^(9′), X′ and Z are as definedabove.

[0238] Step 31

[0239] In Step 31, carboxylic acid (VII) and amino derivative (XIX) arereacted to give intermediate compound (XXa). This step can be conductedby the same method as in Step 1.

[0240] Step 32

[0241] In Step 32, intermediate compound (XXa) is converted to succinicacid derivative (XXIa). This step can be conducted by the same method asin Step 3.

[0242] Step 33

[0243] In Step 33, succinic acid derivative (XXIa) is converted tosulfonic acid derivative of O-protected hydroxamic acid (XIII). Thisstep can be conducted by the same method as in Step 4.

[0244] The sulfonic acid derivative of O-protected hydroxamic acid(XIII) can be also prepared by a method shown in the following Scheme 9,or a method similar to that shown in Scheme 3 for sulfonic acidderivative of hydroxamic acid (I).

[0245] wherein W is as defined for X′ and they may be the same ordifferent, and R¹, R², R¹², R^(6″), X′ and Z are as defined above.

[0246] Step 34

[0247] In Step 34, carboxylic acid (X) and amino derivative (XIX) arereacted to give sulfonic acid derivative (XIIIa). This step can beconducted by the same method as in Step 1.

[0248] Step 35

[0249] In Step 35, sulfonic acid derivative (XIIIa) is converted tosulfonic acid derivative of hydroxamic acid (XIII). This step can beconducted by the same method as in Step 7.

[0250] The carboxylic acid (X) can be prepared according to theaforementioned Scheme 6, and amino derivatives (XVIII) and (XIX) can beprepared by, for example, the method explained in Scheme 11 below.

[0251] The desired substituent R¹ can be introduced without a specialstep but by the methods shown in the aforementioned Scheme 7 and Scheme8 using carboxylic acid (VII) having said substituent. Besides these,for example, it can be also prepared using carboxylic acid (XI) andamino derivative (XIX) by the same method as in Scheme 4 for sulfonicacid derivative of hydroxamic acid (I).

[0252] wherein R¹ is heteroarylthioalkyl, arylthioalkyl,heteroarylalkylthioalkyl, alkylthioalkyl or arylalkylthioalkyl, R^(14′)is as defined for R¹⁴ (except hydrogen), and R², R¹², R^(6″), R^(9′) andZ are as defined above.

[0253] Step 36

[0254] In Step 36, carboxylic acid (XI) and amino derivative (XIX) arereacted to give intermediate compound (XXIIa). This step can beconducted by the same method as in Step 1. The carboxylic acid (XI) tobe the starting material is a compound described in references(JP-A-7-157470 and the like) or a compound prepared by a conventionalmethod based on the references.

[0255] Step 37

[0256] In Step 37, the substituents R^(9′) and R^(14′) of intermediatecompound (XXIIa) are removed to give succinic acid derivative (XXIIb).This step can be conducted by the same method as in Step 11.

[0257] Step 38

[0258] In Step 38, succinic acid derivative (XXIIb) obtained in Step 37is converted to succinic acid derivative (XXIIc) by decarboxylation.This step can be conducted by the same method as in Step 12.

[0259] Step 39

[0260] In Step 39, succinic acid derivative (XXIIb) obtained in Step 37is converted to succinic acid derivative (XXIId) by reaction withformaldehyde in the presence of a secondary amine. This step can beconducted by the same method as in Step 13.

[0261] Step 40

[0262] In Step 40, succinic acid derivative (XXIId) obtained in Step 39is reacted with arylthiol, heteroarylthiol, alkylthiol,heteroarylalkylthiol or arylalkylthiol as a nucleophile to give succinicacid derivative (XXIa) wherein the substituent R¹ is arylthioalkyl,heteroarylthioalkyl, alkylthioalkyl, heteroarylalkylthioalkyl orarylalkylthioalkyl. This step can be conducted by the same method as inStep 14.

[0263] The amino derivatives (XVIII) and (XIX), which are the startingcompounds in Schemes 7-10, can be prepared by the method shown in thefollowing Scheme 11.

[0264] wherein A′ is amino-protecting group such as tert-butoxycarbonyl,benzyloxycarbonyl and the like, and R¹², R^(6′), R^(6″) and Z are asdefined above.

[0265] Step 41

[0266] In Step 41, compound (XXIIIa) and an alcohol derivative such asbenzyl alcohol and the like are reacted to give compound (XXIIIb). Thisstep can be conducted by the same method as in Step 1.

[0267] Step 42

[0268] In Step 42, amino-protecting group of compound (XXIIIb) isremoved to give amino derivative (XVIII), which can be conducted by thesame method as in Step 16.

[0269] Step 43

[0270] In Step 43, compound (XXIIIa) and aminoalkanesulfonic acidderivative: R^(6″)—NH—Z—SO₃H (R^(6″) and Z are as defined above) arereacted to give compound (XXIIIc). This step can be conducted by thesame method as in Step 29.

[0271] Step 44

[0272] In Step 44, amino-protecting group of compound (XXIIIc) isremoved to give amino derivative (XIX), which can be conducted by thesame method as in Step 16.

[0273] The compound (XXIIIa), which is the starting compound in Scheme10, can be prepared by the following method.

[0274] The compound (XXIIIa) can be prepared by protecting amino groupof amino acid of the formula

[0275] with amino protecting group such as tert-butoxycarbonyl group,benzyloxycarbonyl group and the like [e.g., Pepuchidogousei no kiso tojikken, Izumiya et al., Maruzen Shoten, p 16].

[0276] It is not that conversion and the like between varioussubstituents including R³ is possible only in a particular step, butpossible in any step as long as it is under the conditionsnon-influential on other functional groups present in the chemicalstructural formula.

[0277] The sulfonic acid derivative of hydroxamic acid of the presentinvention thus synthesized can be recovered at an optional purity byappropriately applying known separation and purification means, such asconcentration, extraction, chromatography, reprecipitation,recrystallization and the like.

[0278] In addition, pharmacologically acceptable salt and solvate of thesulfonic acid derivative of hydroxamic acid can be prepared by a knownmethod. Moreover, various isomers and the like of the sulfonic acidderivative of hydroxamic acid can be prepared by a known method.

[0279] When the sulfonic acid derivative of hydroxamic acid and apharmacologically acceptable salt thereof of the present invention havea superior LPS inhibitory action on mammals (e.g., human, dog, cat andthe like) and are low toxic.

[0280] Therefore, the sulfonic acid derivative of hydroxamic acid and apharmacologically acceptable salt thereof of the present invention areuseful as an inhibitor of LPS, and are useful for the prophylaxis ortreatment of diseases such as sepsis, MOF, chronic articular rheumatism,Crohn's disease, cachexia, myasthenia gravis, systemic lupuserythematodes, asthma, TYPE I diabetes, psoriasis, other autoimmunediseases, inflammatory diseases and the like.

[0281] When the sulfonic acid derivative of hydroxamic acid or apharmacologically acceptable salt thereof of the present invention isused as a pharmaceutical product, a pharmacologically acceptable carrierand the like are used and can be administered orally or parenterally asa pharmaceutical composition in the form of granule, tablet, capsule,injection, ointment, eye-drop, nose-drop, cream, aerosol and the like.Particularly, the sulfonic acid derivative of hydroxamic acid and apharmacologically acceptable salt thereof are superior inwater-solubility and are preferable for preparation of a water-solublepharmaceutical composition such as injection, eye-drop, nose-drop, agentfor drip and the like.

[0282] The above-mentioned preparation contains an effective amount ofthe sulfonic acid derivative of hydroxamic acid or a pharmacologicallyacceptable salt thereof.

[0283] The dose of the sulfonic acid derivative of hydroxamic acid or apharmacologically acceptable salt thereof varies depending on theadministration route, condition, body weight or age of patients, and thelike, and can be appropriately determined according to theadministration object. For oral administration to an adult, it isgenerally 0.01-1,000 mg/kg body weight/day, preferably 0.05-250 mg/kgbody weight/day, which is preferably administered once a day or inseveral doses a day.

[0284] The present invention is explained in detail in the following byreferring to examples, which are not to be construed as limitative.

[0285]¹H-NMR was measured at 270 MHz or 300 MHz. The chemical shift of¹H-NMR is expressed in relative delta (δ) values in parts per million(ppm) using tetramethylsilane as the internal standard. For the couplingconstant, obvious multiplicity is shown in hertz (Hz) using s (singlet),d (doublet), t (triplet), q (quartet), m (multiplet), dd (doublet ofdoublet), br s (broad singlet) and the like.

EXAMPLE 15-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0286]

[0287] (1) 1,2-dibenzyl 1-tert-butyl4-methyl-1,1,2-(R)-pentanetricarboxylate

[0288] Using (D)-leucine as a starting material and in the same manneras in the method described in JP-A-4-352757, synthesis was performed.

[0289]¹H-NMR (CDCl₃) δ 7.45-7.20 (m, 10H), 5.25-4.93 (m, 4H), 3.68 and3.65 (d, J=9.8 Hz, 1H), 3.25-3.08 (m, 1H), 1.68-1.38 (m, 2H), 1.34 and1.33 (s, 9H), 1.35-1.05 (m, 1H), 0.90, 0.84, 0.83 and 0.78 (d, J=6.4 Hz,6H).

[0290] (2) 4-tert-butoxy-2(R)-isobutyl-3(R orS)-phthalimidomethylsuccinic acid

[0291] Using the title compound of Example 1(1) andN-bromomethylphthalimide and in the same manner as in the methoddescribed in JP-A-4-352757, a crude product was obtained. Purificationwas performed according to the following method. A crude product (607 g,about 1.32 mol) was dissolved in diisopropyl ether (6 L),cyclohexylamine (151 mL, 1.32 mol) was added under ice-cooling, and themixture was stirred for 1.5 hr. The precipitate was collected byfiltration, washed (diisopropyl ether) and air-dried. The obtained solidwas suspended in ethyl acetate (0.4 L), and washed successively with 2Naqueous sulfuric acid solution (1.32 L), water (2 L×2) and saturatedbrine (2 L). The organic layer was dried over anhydrous magnesiumsulfate, and after treatment with active carbon (25 g/70° C./30 min),filtrated. The filtrate was concentrated under reduced pressure to givethe title compound (467.6 g, 91%, 68% de) as an oil.

[0292]¹H-NMR (CDCl₃) δ 7.90-7.65 (m, 4H), 4.13 (dd, J=14.0, 9.1 Hz, 1H),3.77 (dd, J=14.0, 5.4 Hz, 1H), 3.25-3.10 (m, 1H), 2.88-2.75 (m, 1H),1.85-1.60 (m, 2H), 1.35 (s, 9H), 1.35-1.20 (m, 1H), 0.93 (d, J=6.5 Hz,6H).

[0293] (3) N^(α)-(tert-butoxycarbonyl)-L-tyrosine N-methylamide

[0294] To a solution of N-(tert-butoxycarbonyl)-L-tyrosine (300 g, 1.07mol) in DMF (2 L) were successively added methylamine hydrochloride(86.4 g, 1.28 mol), 1-hydroxybenzotriazole monohydrate (163 g, 1.07 mol,hereinafter to be abbreviated as HOBt.H₂O), N-methylmorpholine (258 mL,2.35 mol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimidehydrochloride (245 g, 1.28 mol, hereinafter to be abbreviated asWSCI.HCl), under ice-cooling (internal temperature 10° C.). The reactionmixture was stirred for 70 hr while gradually raising the temperature toroom temperature. The reaction mixture was poured into iced water (10L), and the precipitate was collected by filtration and washed withwater and ether. The obtained precipitate was recrystallized from ethylacetate (7 L) to give the title compound (265 g, 84%) as white crystals.

[0295]¹H-NMR (DMSO-d₆) δ 9.14 (s, 1H), 7.76 (d, J=4.5 Hz, 1H), 7.00 (d,J=8.1 Hz, 2H), 6.77 (d, J=8.4 Hz, 2H), 6.63 (d, J=8.1 Hz, 2H), 4.08-3.85(m, 1H), 2.79 (dd, J=13.7, 4.7 Hz, 1H), 2.70-2.55 (m, 1H), 2.56 (d,J=4.2 Hz, 3H), 1.37 (s, 9H).

[0296] (4) L-tyrosine N-methylamide hydrochloride

[0297] The title compound (160 g, 0.54 mol) of Example 1 (3) wasdissolved in a mixed solvent of chloroform (800 mL) and methanol (400mL), and anisole (295 mL, 2.72 mol) and a 4N hydrochloric acid-dioxanesolution (800 mL) were added under ice-cooling (internal temperature 7°C.). The mixture was stirred at the same temperature for 2 hr and atroom temperature for 2 hr. Diisopropyl ether (2 L) was added to thereaction solution, and the precipitate was collected by filtration,washed with diisopropyl ether, and dried to give the title compound (125g, quantitative determination) as a white solid.

[0298] [α]D²⁴=+75.2 (c=1.0, H₂O).

[0299]¹H-NMR (DMSO-d₆) δ 9.80-9.05 (br, 1H), 8.41 (q, J=4.8 Hz, 1H),8.40-8.00 (br, 3H), 7.00 (d, J=8.4 Hz, 2H), 6.71 (d, J=8.4 Hz, 2H),3.90-3.75 (m, 1H), 2.93 (dd, J=13.8, 6.9 Hz, 1H), 2.87 (dd, J=13.8, 7.2Hz, 1H), 2.58 (d, J=4.8 Hz, 3H).

[0300] (5) tert-butyl3(R)-[2-(4-hydroxyphenyl)-1(S)-(methylcarbamoyl)ethylcarbamoyl]-5-methyl-2(Ror S)-phthalimidomethylhexanoate

[0301] To a solution of the title compound (200 g, 0.51 mol) of Example1 (2) and the title compound (118 g, 0.51 mol) of Example 1 (4) in DMF(1 L) were successively added HOBt.H₂O (78.6 g, 0.51 mol),N-methylmorpholine (113 mL, 1.03 mol) and WSCI.HCl (118 g, 0.62 mol)under ice-cooling (internal temperature 10° C.). The reaction mixturewas stirred for 16 hr while gradually raising the temperature to roomtemperature. The reaction solution was poured into iced water (5 L), andthe precipitate was collected by filtration. The obtained precipitatewas dissolved in ethyl acetate (3 L), and washed successively with 0.5Nhydrochloric acid, water, saturated aqueous sodium hydrogencarbonatesolution, water and saturated brine (1 L each), dried (anhydrousmagnesium sulfate) and concentrated under reduced pressure. The obtainedresidue was recrystallized from ethyl acetate (1.9 L)-diisopropyl ether(1 L) to give the title compound (201 g, 69%) as white crystals.

[0302]¹H-NMR (DMSO-d₆) δ 8.75 (s, 1H), 8.37 (d, J=9.0 Hz, 1H), 7.95-7.70(m, 5H), 7.04 (d, J=8.4 Hz, 2H), 6.46 (d, J=8.4 Hz, 2H), 4.65-4.50 (m,1H), 3.40 (dd, J=13.7, 11.7 Hz, 1H), 2.87 (dd, J=13.7, 4.5 Hz, 1H),2.70-2.50 (m, 3H), 2.59 (d, J=4.8 Hz, 3H), 2.27 (dd, J=13.7, 5.1 Hz,1H), 1.58-1.44 (m, 1H), 1.42-1.25 (m, 1H), 1.09 (s, 9H), 0.90-0.70 (m,1H), 0.84 (d, J=6.6 Hz, 3H), 0.76 (d, J=6.6 Hz, 3H).

[0303] (6) tert-butyl5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanoate cesium salt

[0304] To a solution of the title compound (91.2 g, 161 mmol) of Example1 (5) in DMF (500 mL) were added 1,3-propanesultone (21.7 g, 177 mmol)and cesium carbonate (57.8 g, 177 mmol) at room temperature, and themixture was stirred for 45 hr. Diisopropyl ether (2 L) was added to thereaction solution, and the precipitate was collected by filtration,washed with ethyl acetate and dried to give the title compound (159 g,quantitative determination) as a white solid.

[0305]¹H-NMR (DMSO-d₆) δ 8.43 (d, J=9.0 Hz, 1H), 8.00-7.80 (m, 5H), 7.17(d, J=8.4 Hz, 2H), 6.57 (d, J=8.4 Hz, 2H), 4.70-4.55 (m, 1H), 3.70-3.10(m, 3H), 3.00-2.85 (m, 1H), 2.75-2.35 (m, 3H), 2.61 (d, J=4.5 Hz, 3H),2.16 (t, J=7.4 Hz, 2H), 1.98 (dd, J=13.5, 4.5 Hz, 1H), 1.60-1.42 (m,1H), 1.40-1.20 (m, 3H), 1.09 (s, 9H), 0.90-0.70 (m, 1H), 0.85 (d, J=6.5Hz, 3H), 0.76 (d, J=6.5 Hz, 3H).

[0306] (7)5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanoic acid

[0307] The title compound (159 g, 161 mmol) of Example 1 (6) wassuspended in methylene chloride (500 mL) and trifluoroacetic acid (500mL) was added under ice-cooling (internal temperature 5° C.). Themixture was stirred at room temperature for 4.5 hr. Diisopropyl ether (2L) was added to the reaction solution, and the precipitate was collectedby filtration. The obtained precipitate was recrystallized from 1.2Nhydrochloric acid (3.5 L) to give the title compound (77.7 g, 76%) aswhite crystals.

[0308]¹H-NMR (DMSO-d₆) δ 8.37 (d, J=8.8 Hz, 1H), 7.95-7.80 (m, 5H), 7.17(d, J=8.6 Hz, 2H), 6.57 (d, J=8.6 Hz, 2H), 4.75-4.57 (m, 1H), 3.55-3.35(m, 2H), 3.24 (dd, J=13.5, 11.1 Hz, 1H), 2.93 (dd, J=13.6, 3.9 Hz, 1H),2.72-2.55 (m, 1H), 2.62 (d, J=4.6 Hz, 3H), 2.55-2.42 (m, 2H), 2.22 (t,J=7.4 Hz, 2H), 2.07 (dd, J=13.5, 3.7 Hz, 1H), 1.60-1.20 (m, 4H),0.95-0.75 (m, 1H), 0.84 (d, J=6.5 Hz, 3H), 0.76 (d, J=6.5 Hz, 3H).

[0309] (8) 2-tetrahydropyranyl5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamate sodium salt

[0310] To a solution of the title compound (13.80 g, 21.8 mmol) ofExample 1 (7) in DMF (50 mL) were added successively N-methylmorpholine(4.8 mL, 43.7 mmol), O-2-tetrahydropyranylhydroxylamine (3.07 g, 26.2mmol), HOBt.H₂O (3.35 g, 21.8 mmol) and WSCI.HCl (5.03 g, 26.2 mmol)under ice-cooling (internal temperature 10° C.). The reaction mixturewas stirred for 18 hr while gradually raising the temperature to roomtemperature. The reaction solution was poured into an aqueous solution(500 mL) of sodium dihydrogenphosphate dihydrate (17.00 g, 109 mmol),saturated with sodium chloride and extracted (500 mL×3) with a mixedsolvent of THF-methanol (10/1). Butanol was added to the extractsolution and the mixture was concentrated under reduced pressure.Diisopropyl ether (1 L) was added to the residue, and the precipitatewas collected by filtration and dried to give the title compound (30.20g, quantitative determination) as a white solid.

[0311]¹H-NMR (DMSO-d₆) δ 10.89 and 10.85 (br s, 1H), 8.36 (d, J=8.7 Hz,1H), 8.00-7.88 (m, 1H), 7.88-7.75 (m, 4H), 7.19 (d, J=8.7 Hz, 2H), 6.53(d, J=8.7 Hz, 2H), 4.70-4.55 (m, 1H), 4.52 and 4.37 (br s, 1H),3.75-3.00 (m, 5H), 2.93 (dd, J=13.7, 4.1 Hz, 1H), 2.78-2.58 (m, 2H),2.61 (d, J=4.5 Hz, 3H), 2.58-2.23 (m, 2H), 2.18 (t, J=7.4 Hz, 2H),2.00-1.80 (m, 1H), 1.60-1.20 (m, 10H), 0.90-0.70 (m, 1H), 0.82 (d, J=6.5Hz, 3H), 0.75 (d, J=6.5 Hz, 3H).

[0312] (9)5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0313] The title compound (30.20 g, 21.8 mmol) of Example 1 (8) wassuspended in a mixed solvent of water (50 mL)-methanol (50 mL)-THF (50mL), and 2.4N hydrochloric acid (50 mL) was added at room temperature.The mixture was stirred for 3 hr. Methanol and THF were distilled awayunder reduced pressure from the reaction solution, and the precipitatewas collected by filtration and washed with isopropyl alcohol anddiisopropyl ether. The obtained precipitate was suspended in water (600mL) and neutralized with sodium hydrogencarbonate (1.84 g, 21.8 mmol).The obtained aqueous solution was purified using a synthetic adsorbentcolumn (DIAION HP-20: water, 50% aqueous methanol solution), and thefractions eluted with a 50% aqueous methanol solution were collected andconcentrated under reduced pressure until the precipitate appeared. Theresidue was recrystallized from water-isopropyl alcohol to give thetitle compound (4.01 g, 27%) as white crystals.

[0314] [α]D²⁰=−50.3 (c=1.0, MeOH)

[0315]¹H-NMR (DMSO-d₆) δ 10.28 (br s, 1H), 8.57 (br s, 1H), 8.28 (d,J=8.7 Hz, 1H), 7.90-7.70 (m, 5H), 7.17 (d, J=8.6 Hz, 2H), 6.53 (d, J=8.6Hz, 2H), 4.70-4.52 (m, 1H), 3.50-3.20 (m, 3H), 2.91 (dd, J=13.5, 3.3 Hz,1H), 2.72-2.58 (m, 1H), 2.61 (d, J=4.5 Hz, 3H), 2.50-2.25 (m, 2H), 2.16(t, J=7.3 Hz, 2H), 1.90 (dd, J=13.6, 3.6 Hz, 1H), 1.50-1.20 (m, 4H),0.90-0.65 (m, 1H), 0.82 (d, J=6.5 Hz, 3H), 0.76 (d, J=6.5 Hz, 3H).

EXAMPLE 25-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Potassium Salt

[0316]

[0317] (1) 2-tetrahydropyranyl5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamate potassium salt

[0318] To a solution of the title compound (5.00 g, 7.20 mmol) ofExample 1 (7) in DMF (50 mL) were added successively N-methylmorpholine(1.58 mL, 14.39 mmol), O-2-tetrahydropyranylhydroxylamine (1.26 g, 10.80mmol), HOBt.H₂O (1.10 g, 7.20 mmol) and diisopropylcarbodiimide (1.36 g,10.80 mmol, hereinafter to be abbreviated as DIPCI) under ice-cooling(internal temperature 10° C.). The mixture was stirred for 21 hr whilegradually raising the temperature to room temperature. A solution ofpotassium acetate (0.71 g, 7.20 mmol) in acetic acid (10 mL) was addedto the reaction solution, and after stirring the mixture for 1 hr,diisopropyl ether was added. The precipitate was collected byfiltration. The obtained precipitate was washed with diisopropyl etherand dried to give the title compound (5.82 g, quantitativedetermination) as a white solid.

[0319]¹H-NMR (DMSO-d₆) δ 10.87 and 10.83 (br s, 1H), 8.30 (d, J=8.6 Hz,1H), 7.90-7.70 (m, 5H), 7.18 (d, J=8.6 Hz, 2H), 6.54 (d, J=8.6 Hz, 2H),4.70-4.55 (m, 1H), 4.53 and 4.38 (br s, 1H), 3.75-3.12 (m, 4H),3.12-2.55 (m, 3H), 2.62 (d, J=4.6 Hz, 3H), 2.55-2.22 (m, 2H), 2.18 (t,J=7.3 Hz, 2H), 2.00-1.85 (m, 1H), 1.60-1.15 (m, 10H), 0.90-0.70 (m, 1H),0.82 (d, J=6.6 Hz, 3H), 0.75 (d, J=6.6 Hz, 3H).

[0320] (2)5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid potassium salt

[0321] To a solution of the title compound (5.82 g, about 7.20 mmol) ofExample 2 (1) in methanol (100 mL) was added a solution of 5% hydrogenchloride in methanol (50 mL), and the mixture was stirred at 30° C. for1.5 hr. Diisopropyl ether (450 mL) was added to the reaction solution,and the precipitate was collected by filtration and washed withdiisopropyl ether. The obtained precipitate was recrystallized fromwater-isopropyl alcohol to give the title compound (2.85 g, 58%) aswhite crystals.

[0322]¹H-NMR (DMSO-d₆) δ 10.27 (br s, 1H), 8.55 (br s, 1H), 8.27 (d,J=8.6 Hz, 1H), 7.90-7.70 (m, 5H), 7.17 (d, J=8.6 Hz, 2H), 6.53 (d, J=8.6Hz, 2H), 4.68-4.52 (m, 1H), 3.50-3.20 (m, 3H), 2.91 (dd, J=13.9, 4.0 Hz,1H), 2.75-2.60 (m, 1H), 2.61 (d, J=4.6 Hz, 3H), 2.55-2.25 (m, 2H), 2.17(t, J=7.3 Hz, 2H), 1.94 (dd, J=13.5, 3.6 Hz, 1H), 1.50-1.20 (m, 4H),0.90-0.70 (m, 1H), 0.82 (d, J=6.3 Hz, 3H), 0.76 (d, J=6.3 Hz, 3H).

EXAMPLE 35-methyl-3(R)-{1(R)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0323] [One Kind of Diastereomer of Compound of Example 1]

[0324] (1) N^(α)-(tert-butoxycarbonyl)-D-tyrosine N-methylamide

[0325] Using N-(tert-butoxycarbonyl)-D-tyrosine, and in the same manneras in the method described in Example 1 (3), synthesis was performed.

[0326] (2) D-tyrosine N-methylamide hydrochloride

[0327] Using the title compound of Example 3 (1), and in the same manneras in the method described in Example 1 (4), synthesis was performed.

[0328] [α]D²²=−73.1 (c=1.0, H₂O)

[0329] (3)5-methyl-3(R)-{1(R)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0330] Using the title compound of Example 1 (2) and the title compoundof Example 3 (2), and in the same manner as in the method described inExample 1 (5)-(9), synthesis was performed.

[0331]¹H-NMR (DMSO-d₆) δ 10.43 (s, 1H), 8.66 (s, 1H), 8.37 (d, J=8.4 Hz,1H), 8.01 (d, J=4.8 Hz, 1H), 7.83 (s, 4H), 7.14 (d, J=8.4 Hz, 2H), 6.78(d, J=8.4 Hz, 2H), 4.49-4.42 (m, 1H), 3.98 (dt, J=13.0, 5.9 Hz, 2H),4.02-3.94 (m, 1H), 3.48-3.38 (m, 1H), 3.00 (dd, J=14.2, 4.2 Hz, 1H),2.60 (d, J=4.5 Hz, 3H), 2.00 (dt, J=14.9, 6.5 Hz, 2H), 1.40 (app t,J=10.4 Hz, 1H), 0.85-0.68 (m, 2H), 0.63 (d, J=5.5 Hz, 3H), 0.59 (d,J=5.6 Hz, 3H).

EXAMPLE 45-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0332] [One Kind of Diastereomer of Compound of Example 1]

[0333] (1) 4-tert-butoxy-2(R)-isobutyl-3(R orS)-phthalimidomethylsuccinic acid

[0334] [One Kind of Diastereomer of Compound of Example 1 (2)]

[0335] The title compound of Example 1 (2) was obtained by purificationby column chromatography.

[0336]¹H-NMR (DMSO-d₆) δ 7.89-7.82 (m, 2H), 7.75-7.68 (m, 2H), 4.09 (dd,J=15.4, 10.2 Hz, 1H), 3.83 (dd, J=15.4, 5.9 Hz, 1H), 3.15-3.07 (m, 1H),2.82-2.74 (m, 1H), 1.79-1.60 (m, 2H), 1.54-1.38 (m, 1H), 1.32 (s, 9H),0.94 (d, J=7.4 Hz, 3H), 0.92 (d, J=7.4 Hz, 3H).

[0337] (2) N^(α)-(tert-butoxycarbonyl)-(O-3-sulfopropyl)-L-tyrosineN-methylamide cesium salt

[0338] To a solution of the title compound (10.00 g, 34.0 mmol) ofExample 1 (3) and 1,3-propanesultone (4.56 g, 37.4 mmol) in DMF (100 mL)was added cesium carbonate (12.18 g, 37.4 mmol) at room temperature, andthe mixture was stirred for 15 hr. Diisopropyl ether (300 mL) was addedto the reaction solution, and the precipitate was collected byfiltration, washed with ethyl acetate and dried to give the titlecompound (26.42 g, quantitative determination) as a brown solid.

[0339]¹H-NMR (DMSO-d₆) δ 7.90-7.75 (m, 1H), 7.11 (d, J=8.6 Hz, 2H), 6.80(d, J=8.6 Hz, 2H), 6.90-6.70 (m, 1H), 4.10-3.85 (m, 1H), 3.99 (t, J=6.6Hz, 2H), 2.84 (dd, J=13.8, 4.8 Hz, 1H), 2.65 (dd, J=13.8, 10.1 Hz, 1H),2.60-2.45 (m, 2H), 2.57 (d, J=4.5 Hz, 3H), 2.05-1.90 (m, 2H), 1.30 (s,9H).

[0340] (3) O-3-sulfopropyl-L-tyrosine N-methylamide

[0341] The title compound (26.42 g, about 34.0 mmol) of Example 4 (2)was suspended in methylene chloride (50 mL)—anisole (18.5 mL, 169.9mmol) and trifluoroacetic acid (50 mL) was added to the suspension underice-cooling. The mixture was stirred at the same temperature for 1 hrand at room temperature for 1 hr. Diisopropyl ether (300 mL) was addedto the reaction solution, and the precipitate was collected byfiltration, washed with ethyl acetate and dried to give a crude product(35.96 g) as a pale-brown solid. This was recrystallized from water (35mL)—isopropyl alcohol (150 mL) to give the title compound (8.00 g, 74%)as white crystals.

[0342] [α]D²⁵=+55.4 (C=1.0, H₂O).

[0343]¹H-NMR (DMSO-d₆) δ 8.40-7.80 (br, 3H), 8.30 (q, J=4.5 Hz, 1H),7.12 (d, J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 4.05 (t, J=6.5 Hz, 2H),3.83 (dd, J=7.2, 6.6 Hz, 1H), 2.97 (dd, J=13.8, 6.6 Hz, 1H), 2.86 (dd,J=13.8, 7.2 Hz, 1H), 2.61 (d, J=4.5 Hz, 3H), 2.55 (t, J=7.2 Hz, 3H),2.10-1.90 (m, 2H).

[0344] (4) tert-butyl5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanoate sodium salt

[0345] To a solution of the title compound (1.54 g, 3.95 mmol) ofExample 4 (1) and the title compound (1.70 g, 3.95 mmol) of Example 4(3) in DMF (30 mL) were added successively HOBt.H₂O (0.61 g, 3.95 mmol),N-methylmorpholine (1.73 mL, 15.7 mmol) and WSCI.HCl (0.91 g, 4.74 mmol)under ice-cooling (internal temperature 10° C.), and the mixture wasstirred for 8 hr while gradually raising the temperature to roomtemperature. The reaction solution was poured into iced water, andsodium dihydrogenphosphate dihydrate (1.85 g, 11.85 mmol) was added. Themixture was saturated with sodium chloride, and extracted (100 mL×3)with a mixed solvent of THF-methanol (10/1). Butanol was added to theextract solution and the mixture was concentrated under reducedpressure. Diisopropyl ether was added to the residue, and theprecipitate was collected by filtration and dried to give the titlecompound (1.62 g, 58%) as a white solid.

[0346]¹H-NMR (DMSO-d₆) δ 8.13 (d, J=8.1 Hz, 1H), 7.95-7.83 (m, 4H), 7.70(d, J=4.5 Hz, 1H), 7.06 (d, J=8.4 Hz, 2H), 6.78 (d, J=8.4 Hz, 2H),4.35-4.32 (m, 1H), 3.96 (t, J=6.6 Hz, 2H), 3.82-3.64 (m, 1H), 3.00-2.90(m, 1H), 2.89-2.73 (m, 1H), 2.70-2.60 (m, 1H), 1.95 (dt, J=14.7, 7.8 Hz,2H), 1.57 (m, 1H), 1.42-1.28 (m, 1H), 1.13 (s, 9H), 0.86 (d, J=6.0 Hz,3H), 0.81 (d, J=6.0 Hz, 3H).

[0347] (5)5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanoic acid

[0348] The title compound (1.62 g, 2.28 mmol) of Example 4 (4) wassuspended in methylene chloride (10 mL), and trifluoroacetic acid (10mL) was added under ice-cooling (internal temperature 5° C.). Themixture was stirred at room temperature for 3 hr. Ether was added to thereaction solution under ice-cooling, and the precipitate was collectedby filtration to give the title compound (1.41 g, quantitativedetermination) as a white solid.

[0349]¹H-NMR (DMSO-d₆) δ 8.36 (d, J=8.1 Hz, 1H), 7.92-7.83 (m, 4H), 7.72(d, J=4.2 Hz, 1H), 7.08 (d, J=8.8 Hz, 2H), 6.76 (d, J=8.8 Hz, 2H), 4.39(dd, J=15.0, 7.8 Hz, 1H), 3.92-3.87 (m, 2H), 2.96-2.67 (m, 4H), 1.85(dt, J=14.4, 6.9 Hz, 2H), 1.55 (m, 1H), 0.84 (d, J=6.0 Hz, 3H), 0.80 (d,J=6.0 Hz, 3H).

[0350] (6) O-(2-nitrobenzyl)5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamate sodium salt

[0351] To a solution of the title compound (1.41 g, 2.23 mmol) ofExample 4 (5) in DMF (20 mL) were added successively N-methylmorpholine(1.0 mL, 9.80 mmol), O-2-nitrobenzylhydroxylamine hydrochloride (0.55 g,2.67 mmol), HOBt.H₂O (0.34 g, 2.23 mmol) and WSCI.HCl (0.51 g, 2.67mmol) under ice-cooling (internal temperature 10° C.), and the mixturewas stirred for 48 hr while gradually raising the temperature to roomtemperature. The reaction solution was poured into iced water and sodiumdihydrogenphosphate dihydrate (1.04 g, 6.69 mmol) was added. The mixturewas saturated with sodium chloride and extracted (100 mL×3) with a mixedsolvent of THF-methanol (10/1). Butanol was added to the extractsolution and the mixture was concentrated under reduced pressure.Diisopropyl ether was added to the residue and the precipitate wascollected by filtration and dried to give the title compound (0.35 g,19%) as a white solid.

[0352]¹H-NMR (DMSO-d₆) δ 11.39 (s, 1H), 8.14 (d, J=8.1 Hz, 1H), 8.04 (d,J=8.1 Hz, 1H), 7.81-7.76 (m, 5H), 7.64-7.62 (m, 2H), 7.54-7.51 (m, 1H),7.05 (d, J=8.4 Hz, 2H), 6.74 (d, J=8.4 Hz, 2H), 5.04 (d, J=14.7 Hz, 1H),5.00 (d, J=14.7 Hz, 1H), 4.33-4.30 (m, 1H), 3.92 (t, J=6.6 Hz, 2H),3.73-3.62 (m, 1H), 3.52-3.41 (m, 1H), 2.97-2.78 (m, 2H), 1.90 (dt,J=14.4, 7.2 Hz, 2H), 1.52 (m, 1H), 1.28-1.26 (m, 2H), 0.78 (app d, J=2.7Hz, 6H).

[0353] (7)5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0354] The title compound (350 mg, 0.435 mmol) of Example 4 (6) wassuspended in a mixed solvent of THF-water (9/1), and subjected to lightradiation with a high pressure mercury vapor lamp under ice-cooling for1.5 hr. The reaction mixture was concentrated under reduced pressure.The residue was dissolved in methanol and ether was added to allowprecipitation. The precipitate was recrystallized (diisopropylalcohol-water) to give the title compound (93 mg, 32%) as whitecrystals.

[0355]¹H-NMR (DMSO-d₆) δ 10.58 (s, 1H), 8.75 (s, 1H), 8.12 (d, J=7.8 Hz,1H), 7.89-7.66 (m, 4H), 7.06 (d, J=8.4 Hz, 2H), 6.74 (d, J=6.3 Hz, 2H),4.37-4.29 (m, 1H), 3.94 (t, J=6.4 Hz, 2H), 3.75 (dd, J=14.0, 10.3 Hz,1H), 3.49 (dd, J=13.6, 4.0 Hz, 1H), 2.92 (dd, J=14.0, 6.1 Hz, 1H),2.84-2.73 (m, 2H), 2.56 (d, J=4.5 Hz, 3H), 2.54-2.42 (m, 2H), 1.90 (dt,J=14.8, 7.1 Hz, 2H), 1.57 (app t, J=9.4 Hz, 1H), 1.23-1.20 (m, 2H), 0.76(app d, J=4.5 Hz, 6H).

EXAMPLE 55-methyl-3(R)-{1(R)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0356] [One Kind of Diastereomer of Compound of Example 1]

[0357] (1) N^(α)-(tert-butoxycarbonyl)-(O-3-sulfopropyl)-D-tyrosineN-methylamide

[0358] Using the title compound of Example 3 (1) and in the same manneras in the method described in Example 4 (2), synthesis was performed.

[0359] (2) O-3-sulfopropyl-D-tyrosine N-methylamide

[0360] Using the title compound of Example 5 (1) and in the same manneras in the method described in Example 4 (3), synthesis was performed.

[0361] [α]D²⁷=−55.5 (C=1.0, H₂O)

[0362] (3)5-methyl-3(R)-{1(R)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0363] Using the title compound of Example 4 (1) and the title compoundof Example 5 (2), and in the same manner as in the method described inExample 4 (4)-(7), synthesis was performed.

[0364]¹H-NMR (DMSO-d₆) δ 10.62 (s, 1H), 9.20 (s, 1H), 8.40 (d, J=8.7 Hz,1H), 7.88-7.82 (m, 4H), 7.51 (d, J=4.8 Hz, 1H), 7.08 (d, J=8.4 Hz, 2H),6.77 (d, J=8.4 Hz, 2H), 4.29-4.23 (m, 1H), 3.97 (t, J=6.4 Hz, 2H), 3.76(dd, J=13.7, 9.0 Hz, 1H), 3.56 (dd, J=13.7, 4.4 Hz, 1H), 3.26-3.13 (m,1H), 2.63 (d, J=4.4 Hz, 3H), 2.56-2.49 (m, 2H), 2.44-2.32 (m, 1H), 1.96(dt, J=15.0, 6.4 Hz, 2H), 1.29-1.24 (m, 2H), 0.72 (d, J=5.8 Hz, 3H),0.57-0.44 (m, 1H), 0.56 (d, J=5.5 Hz, 3H).

EXAMPLE 65-methyl-3(S)-{1(R)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0365] [Optical Isomer of Compound of Example 1]

[0366] (1) 1,2-dibenzyl 1-tert-butyl4-methyl-1,1,2-(S)-pentanetricarboxylate

[0367] Using (L)-leucine as a starting material and in the same manneras in the method described in Example 1 (1), synthesis was performed.

[0368] (2) 4-tert-butoxy-2(S)-isobutyl-3(R orS)-phthalimidomethylsuccinic acid

[0369] Using the title compound of Example 6 (1) and in the same manneras in the method described in Example 1 (2), synthesis was performed.

[0370] (3)5-methyl-3(S)-{1(R)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0371] Using the title compound of Example 6 (2) and the title compoundof Example 3 (2), and in the same manner as in the method described inExample 1 (5)-(9), synthesis was performed.

[0372] [α]D²⁰=+46.5 (c=1.02, MeOH)

[0373] The NMR data matched the NMR data of the title compound ofExample 1 (9).

EXAMPLE 75-methyl-3(S)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0374] [One Kind of Diastereomer of Compound of Example 1]

[0375] Using the title compound of Example 6 (2) and the title compoundof Example 1 (4), and in the same manner as in the method described inExample 1 (5)-(9), synthesis was performed.

[0376] The NMR data matched the NMR data of the title compound ofExample 3 (3).

EXAMPLE 85-methyl-3(S)-{1(R)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0377] [One Kind of Diastereomer of Compound of Example 1]

[0378] (1) 4-tert-butoxy-2(S)-isobutyl-3(R orS)-phthalimidomethylsuccinic acid

[0379] [One Kind of Diastereomer of Compound of Example 6 (2)]

[0380] The title compound of Example 6 (2) was obtained by purificationby column chromatography. The NMR data matched the NMR data of the titlecompound of Example 4 (1).

[0381] (2)5-methyl-3(S)-{1(R)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0382] Using the title compound of Example 8 (1) and the title compoundof Example 5 (2), and in the same manner as in the method described inExample 4 (4)-(7), synthesis was performed.

[0383] The NMR data matched the NMR data of the title compound ofExample 4 (7).

EXAMPLE 95-methyl-3(S)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0384] [One Kind of Diastereomer of Compound of Example 1]

[0385] Using the title compound of Example 8 (1) and the title compoundof Example 4 (3), and in the same manner as in the method described inExample 4 (4)-(7), synthesis was performed. The NMR data matched the NMRdata of the title compound of Example 5 (3).

EXAMPLE 105-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(2-sulfoethoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0386]

[0387] (1) N^(α)-(tert-butoxycarbonyl)-(O-2-benzyloxyethyl)-L-tyrosineN-methylamide

[0388] To a solution of the title compound (5.00 g, 16.99 mmol) ofExample 1 (3) in THF (150 mL) were added successively ethylene glycolmonobenzyl ether (7.76 g, 50.96 mmol), triphenylphosphine (13.37 g,50.96 mmol) and diethyl azodicarboxylate (40% toluene solution) (22.19g, 50.96 mmol) under ice-cooling. The mixture was stirred at the sametemperature for 2 hr, and at room temperature for 68 hr. The reactionsolution was concentrated under reduced pressure and purified by flushsilica gel column chromatography (silica gel 150 g, hexane/ethylacetate=5/1, 2/1, 1/1) to give the title compound (7.86 g) as a whitesolid.

[0389]¹H-NMR (CDCl₃) δ 7.45-7.25 (m, 5H), 7.10 (d, J=8.7 Hz, 2H), 6.85(d, J=8.7 Hz, 2H), 5.90-5.50 (br, 1H), 5.20-4.85 (br, 1H), 4.63 (s, 2H),4.30-4.15 (m, 1H), 4.13 (t, J=4.8 Hz, 2H), 3.82 (t, J=4.8 Hz, 2H), 3.03(dd, J=13.7, 6.2 Hz, 1H), 2.93 (dd, J=13.7, 7.7 Hz, 1H), 2.71 (d, J=4.8Hz, 3H), 1.41 (s, 9H).

[0390] (2) N^(α)-(tert-butoxycarbonyl)-(O-2-hydroxyethyl)-L-tyrosineN-methylamide

[0391] To a solution of the title compound (7.86 g, about 11.55 mmol) ofExample 10 (1) in ethanol (300 mL) was added palladium black (0.80 g)under ice-cooling and under a nitrogen atmosphere. After hydrogensubstitution, the mixture was stirred at room temperature for 6 hr. Thecatalyst was removed from the reaction solution by celite filtration andthe residue was concentrated under reduced pressure. The obtainedresidue was purified by flush silica gel column chromatography (silicagel 200 g, chloroform/methanol=50/1, 20/1, 10/1) to give the titlecompound (2.48 g, two step yield from Example 10 (1): 43%) as a whitesolid.

[0392]¹H-NMR (CDCl₃) δ 7.11 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H),6.00-5.60 (br, 1H), 5.30-4.80 (br, 1H), 4.35-4.20 (m, 1H), 4.06 (t,J=4.4 Hz, 2H), 4.02-3.90 (m, 2H), 3.02 (dd, J=13.4, 6.3 Hz, 1H), 2.95(dd, J=13.4, 7.5 Hz, 1H), 2.73 (d, J=4.8 Hz, 3H), 2.15 (t, J=6.0 Hz,1H), 1.41 (s, 9H).

[0393] (3) N^(α)-(tert-butoxycarbonyl)-(O-2-bromoethyl)-L-tyrosineN-methylamide

[0394] To a solution of the title compound (2.48 g, 7.33 mmol) ofExample 10 (2) in methylene chloride (50 mL) were added successivelytriphenylphosphine (2.88 g, 10.99 mmol) and carbon tetrabromide (2.92 g,8.79 mmol) at room temperature. The mixture was stirred at the sametemperature for 15 min. Saturated aqueous sodium hydrogencarbonatesolution (50 mL) was added to the reaction solution, and the mixture wasextracted with chloroform (100 mL). The obtained organic layer waswashed with water (50 mL), dried over anhydrous magnesium sulfate andconcentrated under reduced pressure. The obtained residue was purifiedby flush silica gel column chromatography (silica gel 100 g,chloroform/methanol=50/1, 20/1) to give the title compound (4.11 g) as awhite solid.

[0395]¹H-NMR (CDCl₃) δ 7.11 (d, J=8.6 Hz, 2H), 6.84 (d, J=8.6 Hz, 2H),6.10-5.60 (br, 1H), 5.30-4.80 (br, 1H), 4.30-4.15 (m, 1H), 4.26 (t,J=6.3 Hz, 2H), 3.63 (t, J=6.3 Hz, 2H), 3.10-2.90 (m, 2H), 2.73 (d, J=5.1Hz, 3H), 1.41 (s, 9H).

[0396] (4) N^(α)-(tert-butoxycarbonyl)-(O-2-sulfoethyl)-L-tyrosineN-methylamide sodium salt

[0397] The title compound (4.11 g, about 6.11 mmol) of Example 10 (3)was suspended in a solution of ethanol (100 mL)—water (50 mL) and heatedat 80° C. for dissolution. A solution of sodium sulfite (0.85 g, 6.72mmol) in water (50 mL) was added and the mixture was stirred underreflux for 22 hr. The reaction solution was cooled and ethanol wasdistilled away under reduced pressure. The residue was washed with ethylacetate (100 mL). Butanol was added to the obtained aqueous layer andthe mixture was concentrated under reduced pressure to give the titlecompound (1.65 g, two step yield from Example 10 (3): 56%) as a yellowsolid.

[0398]¹H-NMR (DMSO-d₆) δ 7.90-7.75 (m, 1H), 7.13 (d, J=8.4 Hz, 2H), 6.80(d, J=8.4 Hz, 2H), 6.95-6.80 (m, 1H), 4.16 (t, J=7.7 Hz, 2H), 4.10-3.90(m, 1H), 2.88 (t, J=7.7 Hz, 2H), 2.95-2.75 (m, 1H), 2.75-2.60 (m, 1H),2.57 (d, J=4.5 Hz, 3H), 1.30 (s, 9H).

[0399] (5) O-2-sulfoethyl-L-tyrosine N-methylamide

[0400] A solution of the title compound (1.65 g, about 4.10 mmol) ofExample 10 (4) in trifluoroacetic acid (20 mL) was stirred at roomtemperature for 1 hr. Toluene was added to the reaction solution and themixture was concentrated under reduced pressure to give the titlecompound (2.54 g, quantitative determination).

[0401]¹H-NMR (DMSO-d₆) δ 8.40-8.25 (m, 1H), 8.35-7.90 (br, 3H), 7.13 (d,J=8.4 Hz, 2H), 6.89 (d, J=8.4 Hz, 2H), 4.20 (t, J=7.6 Hz, 2H), 4.00-3.70(m, 1H), 3.10-2.80 (m, 2H), 2.90 (t, J=7.6 Hz, 2H), 2.61 (d, J=4.8 Hz,3H).

[0402] (6) tert-butyl5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(2-sulfoethoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanoate sodium salt

[0403] To a solution of the title compound (1.60 g, 4.10 mmol) ofExample 1 (2) and the title compound (2.54 g, about 4.10 mmol) ofExample 10 (5) in DMF (20 mL) were added successively HOBt.H₂O (0.63 g,4.10 mmol), N-methylmorpholine (1.80 mL, 16.40 mmol) and WSCI.HCl (0.94g, 4.92 mmol) under ice-cooling, and the mixture was stirred for 24.5 hrwhile gradually raising the temperature to room temperature. Thereaction solution was poured into a solution of sodiumdihydrogenphosphate dihydrate (3.20 g, 20.50 mmol) dissolved in water(100 mL) and washed with ethyl acetate (100 mL). The obtained aqueouslayer was saturated with sodium chloride and extracted (100 mL×3) with asolution of THF-methanol (10/1). Butanol was added to the extractsolution and the mixture was concentrated under reduced pressure.Methanol was added to the obtained residue and an insoluble material wasremoved by filtration. The filtrate was concentrated under reducedpressure to give the title compound (2.61 g, 91%) as a yellow solid.

[0404]¹H-NMR (DMSO-d₆) δ 8.45 (d, J=8.9 Hz, 1H), 8.00-7.80 (m, 5H), 7.19(d, J=8.6 Hz, 2H), 6.57 (d, J=8.6 Hz, 2H), 4.75-4.60 (m, 1H), 3.80-3.60(m, 2H), 3.30-3.15 (m, 1H), 3.00-2.90 (m, 1H), 2.80-2.40 (m, 3H), 2.62(d, J=4.5 Hz, 3H), 2.35-2.15 (m, 2H), 2.00-1.85 (m, 1H), 1.60-1.20 (m,2H), 1.09 (s, 9H), 0.90-0.75 (m, 1H), 0.85 (d, J=6.4 Hz, 3H), 0.76 (d,J=6.4 Hz, 3H).

[0405] (7)5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(2-sulfoethoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanoic acid

[0406] The title compound (2.61 g, 3.75 mmol) of Example 10 (6) wassuspended in trifluoroacetic acid (20 mL) and the mixture was stirred atroom temperature for 4 hr. Diethyl ether (100 mL) was added to thereaction solution, and the precipitate was collected by filtration togive the title compound (2.20 g, 95%) as a white solid.

[0407]¹H-NMR (DMSO-d₆) δ 13.00-11.60 (br, 1H), 8.41 (d, J=8.7 Hz, 1H),8.00-7.75 (m, 5H), 7.18 (d, J=8.6 Hz, 2H), 6.56 (d, J=8.6 Hz, 2H),4.75-4.60 (m, 1H), 3.78-3.60 (m, 2H), 3.22 (dd, J=13.6, 11.3 Hz, 1H),2.94 (dd, J=13.8, 4.0 Hz, 1H), 2.75-2.60 (m, 1H), 2.62 (d, J=4.4 Hz,3H), 2.60-2.42 (m, 2H), 2.30-2.15 (m, 2H), 2.02 (dd, J=13.6, 4.1 Hz,1H), 1.60-1.40 (m, 1H), 1.40-1.20 (m, 1H), 0.90-0.70 (m, 1H), 0.84 (d,J=6.5 Hz, 3H), 0.76 (d, J=6.5 Hz, 3H).

[0408] (8) 2-tetrahydropyranyl5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(2-sulfoethoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamate sodium salt

[0409] To a solution of the title compound (2.20 g, 3.56 mmol) ofExample 10 (7) in DMF (50 mL) were added successively N-methylmorpholine(0.78 mL, 7.12 mmol), O-2-tetrahydropyranylhydroxylamine (0.50 g, 4.27mmol), HOBt.H₂O (0.55 g, 3.56 mmol) and WSCI.HCl (0.82 g, 4.27 mmol)under ice-cooling, and the mixture was stirred for 16 hr while graduallyraising the temperature to room temperature. The reaction solution waspoured into a solution of sodium dihydrogenphosphate dihydrate (2.78 g,17.81 mmol) in water (200 mL), saturated with sodium chloride, andextracted (200 mL×1, 100 mL×3) with a mixed solvent of THF-methanol(10/1). Butanol was added to the extract solution and the mixture wasconcentrated under reduced pressure. Diethyl ether was added to theresidue, and the precipitate was collected by filtration and dried togive the title compound (4.50 g, quantitative determination) as a whitesolid.

[0410]¹H-NMR (DMSO-d₆) δ 10.89 and 10.84 (br s, 1H), 8.37 (d, J=9.0 Hz,1H), 8.00-7.87 (m, 1H), 7.87-7.75 (m, 4H), 7.19 (d, J=8.3 Hz, 2H), 6.52(d, J=8.3 Hz, 2H), 4.70-4.58 (m, 1H), 4.53 and 4.37 (br s, 1H),3.75-3.25 (m, 3H), 3.25-3.12 (m, 1H), 3.12-2.88 and 2.75-2.60 (m, 3H),2.61 (d, J=4.5 Hz, 3H), 2.60-2.10 (m, 4H), 1.90-1.75 (m, 1H), 1.60-1.20(m, 8H), 0.90-0.70 (m, 1H), 0.82 (d, J=6.5 Hz, 3H), 0.75 (d, J=6.5 Hz,3H).

[0411] (9)5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(2-sulfoethoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0412] The title compound (4.50 g, about 3.56 mmol) of Example 10 (8)was suspended in a solution of water (20 mL)—methanol (40 mL)—THF (40mL) and 1N hydrochloric acid (20 mL) was added. The mixture was stirredfor 15 hr at room temperature and methanol and THF were distilled awayunder reduced pressure from the reaction solution. Water (300 mL) and 1Naqueous sodium hydrogencarbonate solution (20 mL) were added to theresidue for neutralization. The obtained solution was purified byreverse phase column chromatography (Fuji Silysia Chemical ChromatorexODS DM-1020T: 70 g, water/methanol=100/0, 10/1, 5/1), butanol was addedto the eluate and the mixture was concentrated under reduced pressure.The residue was recrystallized from water-isopropanol to give the titlecompound (0.73 g, 31%) as white crystals.

[0413]¹H-NMR (DMSO-d₆) δ 10.27 (br s, 1H), 8.57 (br s, 1H), 8.28 (d,J=8.7 Hz, 1H), 7.95-7.75 (m, 5H), 7.18 (d, J=8.6 Hz, 2H), 6.52 (d, J=8.6Hz, 2H), 4.75-4.55 (m, 1H), 3.75-3.54 (m, 2H), 3.28 (dd, J=13.5, 11.3Hz, 1H), 2.92 (dd, J=13.6, 3.9 Hz, 1H), 2.72-2.55 (m, 1H), 2.61 (d,J=4.5 Hz, 3H), 2.50-2.28 (m, 2H), 2.28-2.10 (m, 2H), 1.84 (dd, J=13.5,3.9 Hz, 1H), 1.50-1.20 (m, 2H), 0.90-0.70 (m, 1H), 0.82 (d, J=6.5 Hz,3H), 0.76 (d, J=6.5 Hz, 3H).

EXAMPLE 115-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(4-sulfobutoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0414]

[0415] (1) N^(α)-(tert-butoxycarbonyl)-(O-4-sulfobutyl)-L-tyrosineN-methylamide cesium salt

[0416] Using the title compound of Example 1 (3) and 1,4-butanesultone,and in the same manner as in the method described in Example 4 (2),synthesis was performed.

[0417] (2) O-4-sulfobutyl-L-tyrosine N-methylamide

[0418] Using the title compound of Example 11 (1), and in the samemanner as in the method described in Example 4 (3), synthesis wasperformed.

[0419]¹H-NMR (DMSO-d₆) δ 8.40-8.25 (m, 1H), 8.40-7.90 (br, 3H), 7.11 (d,J=8.6 Hz, 2H), 6.89 (d, J=8.6 Hz, 2H), 4.10-3.70 (m, 3H), 3.05-2.78 (m,2H), 2.61 (d, J=4.6 Hz, 3H), 2.55-2.35 (m, 2H), 1.90-1.50 (m, 4H).

[0420] (3)5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(4-sulfobutoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0421] Using the title compound of Example 1 (2) and the title compoundof Example 11 (2), and in the same manner as in the method described inExample 10 (6)-(9), synthesis was performed.

[0422]¹H-NMR (DMSO-d₆) δ 10.27 (br s, 1H), 8.56 (br s, 1H), 8.28 (d,J=9.0 Hz, 1H), 7.95-7.75 (m, 5H), 7.18 (d, J=8.6 Hz, 2H), 6.54 (d, J=8.6Hz, 2H), 4.70-4.55 (m, 1H), 3.45-3.15 (m, 3H), 2.92 (dd, J=13.4, 3.2 Hz,1H), 2.72-2.55 (m, 1H), 2.62 (d, J=4.6 Hz, 3H), 2.50-2.38 (m, 1H),2.38-2.25 (m, 1H), 2.21 (t, J=7.8 Hz, 2H), 1.81 (dd, J=13.5, 3.8 Hz,1H), 1.50-1.20 (m, 4H), 1.10-0.85 (m, 2H), 0.85-0.70 (m, 1H), 0.83 (d,J=6.5 Hz, 3H), 0.75 (d, J=6.5 Hz, 3H).

EXAMPLE 125-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(5-sulfopentoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0423]

[0424] (1) N^(α)-(tert-butoxycarbonyl)-(O-5-chloropentyl)-L-tyrosineN-methylamide

[0425] A solution of the title compound (10.00 g, 34.0 mmol) of Example1 (3), 1-bromo-5-chloropentane (5.0 mL, 38.0 mmol), K₂CO₃ (2.36 g, 17.1mmol) in DMF (100 mL) was stirred at 70° C. for 22 hr. After allowing tocool, the solvent was distilled away under reduced pressure and waterwas added. The mixture was extracted with ethyl acetate, washed withsaturated brine, and dried over magnesium sulfate. The solvent wasdistilled away and the residue was purified by silica gel columnchromatography (CHCl₃) to give the title compound (7.56 g, 56%).

[0426]¹H-NMR (DMSO-d₆) δ 7.99-7.74 (m, 1H), 7.12 (d, J=8.4 Hz, 2H), 6.83(m, 1H), 6.81 (d, J=8.4 Hz, 2H), 4.11-3.99 (m, 1H), 3.92 (t, J=6.3 Hz,2H), 3.65 (t, J=6.6 Hz, 2H), 2.89-2.75 (m, 1H), 2.74-2.45 (m, 1H), 2.59(m, 3H), 1.90-1.43 (m, 6H), 1.35-1.15 (m, 9H).

[0427] (2) N^(α)-(tert-butoxycarbonyl)-(O-5-sulfopentyl)-L-tyrosineN-methylamide sodium salt

[0428] Using the title compound of Example 12 (1), and in the samemanner as in the method described in Example 10 (4), synthesis wasperformed.

[0429]¹H-NMR (DMSO-d₆) δ 7.95-7.75 (br, 1H), 7.11 (d, J=8.4 Hz, 2H),6.87-6.83 (m, 1H), 6.81 (d, J=8.4 Hz, 2H), 4.50-4.21 (br, 1H), 4.10-3.98(m, 1H), 3.98-3.77 (m, 2H), 2.92-2.78 (m, 1H), 2.70-2.45 (m, 1H), 2.59(m, 3H), 2.44-2.30 (m, 2H), 1.79-1.36 (m, 6H), 1.35-1.15 (m, 8H).

[0430] (3) O-5-sulfopentyl-L-tyrosine N-methylamide

[0431] Using the title compound of Example 12 (2), and in the samemanner as in the method described in Example 10 (5), synthesis wasperformed.

[0432]¹H-NMR (DMSO-d₆) δ 8.35-8.24 (br, 1H), 8.22-8.01 (br, 2H), 7.11(d, J=8.4 Hz, 2H), 6.90 (d, J=8.4 Hz, 2H), 3.93 (t, J=6.3 Hz, 2H),3.90-3.74 (m, 1H), 3.66-3.52 (m, 1H), 3.50-3.30 (m, 2H), 3.07-2.79 (m,1H), 2.62 (d, J=4.5 Hz, 2H), 2.45-2.32 (m, 1H), 1.80-1.39 (m, 7H).

[0433] (4)5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(5-sulfopentoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0434] Using the title compound of Example 1 (2) and the title compoundof Example 12 (3), and in the same manner as in the method described inExample 10 (6)-(9), synthesis was performed.

[0435]¹H-NMR (DMSO-d₆) δ 10.27 (br, 1H), 8.56 (br, 1H), 8.28 (d, J=9.0Hz, 1H), 7.88-7.80 (br, 5H), 7.19 (d, J=8.7 Hz, 2H), 6.53 (d, J=8.7 Hz,2H), 4.67-4.57 (m, 1H), 3.40-3.18 (m, 4H), 2.98-2.81 (m, 1H), 2.70-2.51(m, 4H), 2.49-2.37 (m, 1H), 2.36-2.21 (m, 2H), 1.85-1.71 (m, 1H),1.48-1.20 (m, 4H), 1.08-0.82 (m, 5H), 0.82 (d, J=6.3 Hz, 3H), 0.75 (d,J=6.3 Hz, 3H).

EXAMPLE 135-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic Acid Sodium Salt

[0436]

[0437] (1) 4-tert-butoxy-2(R)-isobutyl-3(R orS)-(2-naphthyl)methylsuccinic acid

[0438] Using the title compound of Example 1 (1) and 2-naphthyl bromide,and in the same manner as in the method described in Example 1 (2),synthesis was performed. For purification, flush column chromatographyand recrystallization (hexane) were conducted.

[0439]¹H-NMR (CDCl₃) δ 7.80-7.73 (m, 3H), 7.61 (s, 1H), 7.47-7.39 (m,2H), 7.28 (d, J=1.8 Hz, 1H), 3.07-2.95 (m, 3H), 2.82 (m, 1H), 1.82-1.72(m, 2H), 1.65-1.62 (m, 1H), 1.22 (s, 9H), 0.93 (d, J=6.3 Hz, 3H), 0.91(d, J=6.3 Hz, 3H).

[0440] (2)5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic acid sodium salt

[0441] Using the title compound of Example 13 (1) and the title compoundof Example 4 (3), and in the same manner as in the method described inExample 10 (6)-(9), synthesis was performed.

[0442]¹H-NMR (DMSO-d₆) δ 10.13 (br s, 1H), 8.56 (br s, 1H), 8.31 (d,J=8.7 Hz, 1H), 7.90-7.65 (m, 4H), 7.50-7.35 (m, 2H), 7.26 (s, 1H), 7.20(d, J=8.6 Hz, 2H), 6.94 (dd, J=8.4, 1.5 Hz, 1H), 6.59 (d, J=8.6 Hz, 2H),4.70-4.55 (m, 1H), 3.50-3.20 (m, 3H), 2.90 (dd, J=13.6, 3.9 Hz, 1H),2.72 (dd, J=13.6, 11.5 Hz, 1H), 2.61 (d, J=4.5 Hz, 3H), 2.58-2.40 (m,1H), 2.30-2.20 (m, 1H), 2.20 (t, J=7.3 Hz, 2H), 1.94-1.80 (m, 1H),1.60-1.20 (m, 4H), 1.00-0.80 (m, 1H), 0.85 (d, J=6.5 Hz, 3H), 0.77 (d,J=6.5 Hz, 3H).

EXAMPLE 145-methyl-3(R)-{1(S)-phenylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0443]

[0444] (1) N^(α)-(tert-butoxycarbonyl)-(O-tert-butyl)-L-tyrosineN-phenylamide

[0445] Using N-(tert-butoxycarbonyl)-(O-tert-butyl)-L-tyrosine andaniline, and in the same manner as in the method described in Example 1(3), synthesis was performed.

[0446]¹H-NMR (DMSO-d₆) δ 9.96 (br s, 1H), 7.56 (d, J=7.5 Hz, 2H), 7.30(t, J=8.0 Hz, 2H), 7.21 (d, J=8.3 Hz, 2H), 7.09 (d, J=8.1 Hz, 1H), 7.04(t, J=7.4 Hz, 1H), 6.86 (d, J=8.3 Hz, 2H), 4.40-4.12 (m, 1H), 2.93 (dd,J=13.4, 4.8 Hz, 1H), 2.80 (dd, J=13.4, 10.1 Hz, 1H), 1.32 (s, 9H), 1.24(s, 9H).

[0447] (2) L-tyrosine N-phenylamide hydrochloride

[0448] Using the title compound of Example 14 (1) and in the same manneras in the method described in Example 1 (4), synthesis was performed.

[0449]¹H-NMR (DMSO-d₆) δ 10.71 (br s, 1H), 9.37 (br s, 1H), 8.60-8.10(br, 3H), 7.57 (d, J=7.5 Hz, 2H), 7.34 (t, J=8.0 Hz, 2H), 7.10 (t, J=7.5Hz, 1H), 7.09 (d, J=8.4 Hz, 2H), 6.69 (d, J=8.4 Hz, 2H), 4.30-4.05 (m,1H), 3.09 (dd, J=13.8, 6.6 Hz, 1H), 2.99 (dd, J=13.8, 7.2 Hz, 1H).

[0450] (3)5-methyl-3(R)-{1(S)-phenylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0451] Using the title compound of Example 1 (2) and the title compoundof Example 14 (2), and in the same manner as in the method described inExample 1 (5)-(9), synthesis was performed.

[0452]¹H-NMR (DMSO-d₆) δ 10.27 (br s, 1H), 10.11 (br s, 1H), 8.80-8.30(br, 1H), 8.43 (d, J=8.4 Hz, 1H), 7.90-7.80 (m, 4H), 7.61 (d, J=7.5 Hz,2H), 7.33 (t, J=7.8 Hz, 2H), 7.26 (d, J=8.7 Hz, 2H), 7.06 (t, J=7.4 Hz,1H), 6.56 (d, J=8.7 Hz, 2H), 4.90-4.80 (m, 1H), 3.50-3.20 (m, 3H), 3.04(dd, J=13.2, 3.6 Hz, 1H), 2.82-2.68 (m, 1H), 2.60-2.45 (m, 1H),2.42-2.29 (m, 1H), 2.16 (t, J=7.4 Hz, 2H), 1.95 (dd, J=13.6, 3.9 Hz,1H), 1.55-1.20 (m, 4H), 0.90-0.75 (m, 1H), 0.84 (d, J=6.6 Hz, 3H), 0.73(d, J=6.6 Hz, 3H).

EXAMPLE 155-methyl-3(R)-[2-phenyl-1(S)-(sulfomethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0453]

[0454] (1) N-(tert-butoxycarbonyl)-L-phenylalanine benzyl ester

[0455] To a solution of N-(tert-butoxycarbonyl)-L-phenylalanine (30.0 g,113 mmol) and benzyl alcohol (14.0 mL, 136 mmol) in methylene chloride(200 mL), were added successively 4-dimethylaminopyridine (1.38 g, 11.3mmol) and WSCI.HCl (26.0 g, 136 mmol) under ice-cooling, and the mixturewas stirred for 63 hr while gradually raising the temperature to roomtemperature. The solvent was distilled away from the reaction solutionunder reduced pressure, and water (200 mL) was added to the residue. Themixture was extracted with ethyl acetate (400 mL). The obtained extractsolution was washed with 0.5N hydrochloric acid, water, saturatedaqueous sodium hydrogencarbonate solution, water and saturated brine(each 200 mL), and dried (anhydrous magnesium sulfate) and concentratedunder reduced pressure. The obtained residue was recrystallized fromhexane to give the title compound (33.1 g, 82%) as white crystals.

[0456]¹H-NMR (CDCl₃) δ 7.45-6.90 (m, 10H), 5.17 (d, J=12.3 Hz, 1H), 5.10(d, J=12.3 Hz, 1H), 5.05-4.85 (m, 1H), 4.75-4.55 (m, 1H), 3.20-2.85 (m,2H), 1.41 (s, 9H).

[0457] (2) L-phenylalanine benzyl ester hydrochloride

[0458] To a solution of the title compound (17.8 g, 50.1 mmol) ofExample 15 (1) in chloroform (60 mL) was added 4N hydrochloricacid-dioxane solution (40 mL) under ice-cooling, and the mixture wasstirred at room temperature for 4 hr. Diethyl ether (100 mL) was addedto the reaction solution, and the precipitate was collected byfiltration, washed with diethyl ether and dried to give the titlecompound (13.7 g, 94%) as a white solid.

[0459]¹H-NMR (DMSO-d₆) δ 8.75 (br s, 3H), 7.45-7.15 (m, 10H), 5.16 (d,J=12.4 Hz, 1H), 5.11 (d, J=12.4 Hz, 1H), 4.32 (dd, J=7.8, 5.6 Hz, 1H),3.23 (dd, J=14.0, 5.6 Hz, 1H), 3.09 (dd, J=14.0, 7.8 Hz, 1H).

[0460] (3) tert-butyl3(R)-[1(S)-benzyloxycarbonyl-2-phenylethylcarbamoyl]-5-methyl-2(R orS)-phthalimidomethylhexanoate

[0461] To a solution of the title compound (10.0 g, 25.7 mmol) ofExample 1 (2) and the title compound (7.49 g, 25.7 mmol) of Example 15(2) in DMF (50 mL) were added successively N-methylmorpholine (8.5 mL,77.0 mmol), HOBt.H₂O (3.93 g, 25.7 mmol) and WSCI.HCl (5.91 g, 30.8mmol) under ice-cooling, and the mixture was stirred for 14 hr whilegradually raising the temperature to room temperature. The reactionsolution was poured into iced water (200 mL) and the precipitate wascollected by filtration. The obtained precipitate was dissolved in ethylacetate (300 mL) and washed successively with 0.5N hydrochloric acid,water, saturated aqueous sodium hydrogencarbonate solution, water andsaturated brine (each 100 mL). It was dried (anhydrous magnesiumsulfate) and concentrated under reduced pressure. The obtained residuewas recrystallized from ethyl acetate-hexane to give the title compound(12.3 g, 76%) as white crystals.

[0462]¹H-NMR (CDCl₃) δ 7.90-7.80 (m, 2H), 7.80-7.68 (m, 2H), 7.40-7.05(m, 10H), 6.70 (d, J=8.2 Hz, 1H), 5.19 (d, J=12.2 Hz, 1H), 5.13 (d,J=12.2 Hz, 1H), 5.04 (ddd, J=8.6, 8.2, 5.5 Hz, 1H), 3.46 (dd, J=14.2,5.4 Hz, 1H), 3.39 (dd, J=14.2, 7.1 Hz, 1H), 3.30 (dd, J=14.1, 5.5 Hz,1H), 3.06 (dd, J=14.1, 8.6 Hz, 1H), 2.86 (ddd, J=9.7, 7.1, 5.4 Hz, 1H),2.60 (ddd, J=10.8, 9.8, 3.4 Hz, 1H), 1.70-1.55 (m, 1H), 1.55-1.35 (m,1H), 1.25 (s, 9H), 1.10-0.95 (m, 1H), 0.79 (d, J=6.4 Hz, 3H), 0.78 (d,J=6.4 Hz, 3H).

[0463] (4)3(R)-[1(S)-benzyloxycarbonyl-2-phenylethylcarbamoyl]-5-methyl-2(R orS)-phthalimidomethylhexanoic acid

[0464] To a solution of the title compound (12.0 g, 19.1 mmol) ofExample 15 (3) in methylene chloride (10 mL) was added trifluoroaceticacid (20 mL) under ice-cooling, and the mixture was stirred at roomtemperature for 6 hr. The solvent was distilled away under reducedpressure from the reaction solution, and precipitation with diethylether-hexane was conducted to give the title compound (10.9 g,quantitative determination) as a white powder.

[0465]¹H-NMR (DMSO-d₆) δ 12.35 (br s, 1H), 8.66 (d, J=8.4 Hz, 1H),7.95-7.80 (m, 4H), 7.45-7.20 (m, 7H), 7.20-7.05 (m, 2H), 6.95-6.80 (m,1H), 5.14 (d, J=12.5 Hz, 1H), 5.09 (d, J=12.5 Hz, 1H), 4.85-4.70 (m,1H), 3.45-3.30 (m, 1H), 3.19 (dd, J=13.7, 4.8 Hz, 1H), 2.89 (dd, J=13.7,11.0 Hz, 1H), 2.65 (ddd, J=10.8, 5.1, 5.1 Hz, 1H), 2.59-2.38 (m, 2H),1.60-1.40 (m, 1H), 1.40-1.20 (m, 1H), 0.90-0.75 (m, 1H), 0.74 (d, J=6.6Hz, 3H), 0.69 (d, J=6.6 Hz, 3H).

[0466] (5) 2-tetrahydropyranyl3(R)-[1(S)-benzyloxycarbonyl-2-phenylethylcarbamoyl]-5-methyl-2(R orS)-phthalimidomethylhexanohydroxamate

[0467] To a solution of the title compound (10.90 g, 19.1 mmol) ofExample 15 (4) in DMF (50 mL) were added successively N-methylmorpholine(2.1 mL, 19.1 mmol), 2-tetrahydropyranylhydroxylamine (2.69 g, 23.0mmol), HOBt.H₂O (2.93 g, 19.1 mmol) and WSCI.HCl (4.40 g, 23.0 mmol)under ice-cooling, and the mixture was stirred for 14 hr while graduallyraising the temperature to room temperature. The reaction solution waspoured into iced water (200 mL), and the precipitate was collected byfiltration. The obtained precipitate was washed with water and diethylether, and dried to give the title compound (11.97 g, 93%) as a whitesolid.

[0468]¹H-NMR (DMSO-d₆) δ 10.93 and 10.88 (br s, 1H), 8.70-8.55 (m, 1H),7.95-7.75 (m, 4H), 7.40-7.20 (m, 7H), 7.15-7.00 (m, 2H), 6.90-6.75 (m,1H), 5.13 (d, J=12.6 Hz, 1H), 5.09 (d, J=12.6 Hz, 1H), 4.85-4.70 (m,1H), 4.53 and 4.37 (br s, 1H), 3.75-3.27 (m, 2H), 3.19 (dd, J=13.8, 4.8Hz, 1H), 3.10-2.65 (m, 1H), 2.88 (dd, J=13.8, 11.1 Hz, 1H), 2.60-2.35(m, 2H), 2.24 (ddd, J=13.9, 13.7, 4.1 Hz, 1H), 1.65-1.20 (m, 8H),0.90-0.75 (m, 1H), 0.72 (d, J=6.3 Hz, 3H), 0.68 (d, J=6.3 Hz, 3H).

[0469] (6) 2-tetrahydropyranyl3(R)-[1(S)-carboxy-2-phenylethylcarbamoyl]-5-methyl-2(R orS)-phthalimidomethylhexanohydroxamate

[0470] The title compound (11.97 g, 17.9 mmol) of Example 15 (5) wasdissolved in a mixed solvent of methanol (100 mL)—DMF (150 mL) and 10%palladium-carbon catalyst (1.20 g) was added under ice-cooling. Afterhydrogen substitution, the mixture was stirred at room temperature for3.5 hr. The catalyst was removed from the reaction solution by celitefiltration. The filtrate was concentrated under reduced pressure andwater was added to the obtained residue. The precipitate was collectedby filtration, washed with water and dried to give the title compound(9.17 g, 89%) as a white solid.

[0471]¹H-NMR (DMSO-d₆) δ 13.50-11.50 (br, 1H), 10.93 and 10.88 (br s,1H), 8.60-8.35 (m, 1H), 7.95-7.75 (m, 4H), 7.40-7.20 (m, 2H), 7.15-7.00(m, 2H), 6.87-6.70 (m, 1H), 4.70-4.57 (m, 1H), 4.53 and 4.37 (br s, 1H),3.75-3.20 (m, 2H), 3.15 (dd, J=13.7, 4.2 Hz, 1H), 3.10-2.65 (m, 1H),2.81 (dd, J=13.7, 11.5 Hz, 1H), 2.60-2.35 (m, 2H), 2.21 (ddd, J=13.9,13.7, 4.1 Hz, 1H), 1.70-1.10 (m, 8H), 0.95-0.70 (m, 1H), 0.82 (d, J=6.3Hz, 3H), 0.76 (d, J=6.3 Hz, 3H).

[0472] (7) 2-tetrahydropyranyl5-methyl-3(R)-[2-phenyl-1(S)-(sulfomethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamate sodium salt

[0473] To a solution of the title compound (5.79 g, 9.99 mmol) ofExample 15 (6) in DMF (100 mL) were added successivelyaminomethanesulfonic acid (1.33 g, 12.0 mmol),3-hydroxy-3,4-dihydro-4-oxo-1,2,3-benzotriazine (1.63 g, 9.99 mmol,hereinafter to be abbreviated as HOOBt), N-methylmorpholine (1.1 mL,9.99 mmol) and WSCI.HCl (2.30 g, 12.0 mmol) under ice-cooling. Themixture was stirred for 14 hr while gradually raising the temperature toroom temperature. The reaction solution was poured into a solution ofsodium dihydrogenphosphate dihydrate (7.79 g, 49.9 mmol) in water (400mL), saturated with sodium chloride, and extracted (500 mL×3) with amixed solvent of THF-methanol (10/1). Butanol was added to the extractsolution and the mixture was concentrated under reduced pressure.Diisopropyl ether (1L) was added to the residue, and the precipitate wascollected by filtration and dried to give the title compound (37.80 g,quantitative determination) as a white solid.

[0474]¹H-NMR (DMSO-d₆) δ 10.90-10.75 (m, 1H), 8.40-8.25 (m, 1H),8.12-8.00 (m, 1H), 7.90-7.75 (m, 4H), 7.40-7.25 (m, 2H), 7.05-6.90 (m,2H), 6.70-6.55 (m, 1H), 4.85-4.70 (m, 1H), 4.60-4.30 (m, 1H), 4.10-3.10(m, 5H), 3.10-2.20 (m, 5H), 2.00-1.80 (m, 1H), 1.70-1.15 (m, 8H),0.95-0.70 (m, 1H), 0.83 (d, J=6.3 Hz, 3H), 0.74 (d, J=6.3 Hz, 3H).

[0475] (8)5-methyl-3(R)-[2-phenyl-1(S)-(sulfomethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0476] The title compound (37.80 g, about 9.99 mmol) of Example 15 (7)was suspended in a mixed solvent of water (200 mL)—methanol (400 mL)—THF(200 mL) and 1N hydrochloric acid (200 mL) was added at roomtemperature. The mixture was stirred for 8 hr at the same temperature.Methanol and THF were distilled away under reduced pressure from thereaction solution. The precipitate was collected by filtration andwashed with isopropyl alcohol and diisopropyl ether. The obtainedprecipitate was suspended in water (250 mL), and neutralized with sodiumhydrogencarbonate (0.84 g, 9.99 mmol). The obtained aqueous solution waspurified by synthetic adsorbent column (DIAION HP-20: water, 50% aqueousmethanol solution), and the fractions eluted with a 50% aqueous methanolsolution were collected and concentrated under reduced pressure untilthe precipitate appeared. The residue was recrystallized fromwater-isopropyl alcohol to give the title compound (1.37 g, 22%) aswhite crystals.

[0477]¹H-NMR (DMSO-d₆) δ 10.27 (br s, 1H), 8.56 (br s, 1H), 8.29 (d,J=9.0 Hz, 1H), 8.10-7.95 (m, 1H), 7.95-7.80 (m, 4H), 7.40-7.30 (m, 2H),7.10-6.90 (m, 2H), 6.70-6.55 (m, 1H), 4.85-4.70 (m, 1H), 4.01 (dd,J=13.0, 6.6 Hz, 1H), 3.81 (dd, J=13.0, 5.3 Hz, 1H), 3.50-3.20 (m, 1H),3.12 (dd, J=13.7, 3.2 Hz, 1H), 2.80-2.60 (m, 1H), 2.50-2.32 (m, 2H),1.97-1.80 (m, 1H), 1.55-1.25 (m, 2H), 0.90-0.70 (m, 1H), 0.84 (d, J=6.6Hz, 3H), 0.75 (d, J=6.6 Hz, 3H).

EXAMPLE 165-methyl-3(R)-[2-phenyl-1(R)-(sulfomethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0478] [One Kind of Diastereomer of Compound of Example 15]

[0479] (1) 2-tetrahydropyranyl5-methyl-3(R)-[2-phenyl-1(R)-(sulfomethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-(phthalimidomethyl)hexanohydroxamate sodium salt

[0480] To a solution of the title compound (1.00 g, 1.73 mmol) ofExample 15 (6) in DMF (20 mL) were added successivelyaminomethanesulfonic acid (0.23 g, 2.07 mmol), N-methylmorpholine (0.42mL, 3.80 mmol), HOBt.H₂O (0.26 g, 1.73 mmol) and WSCI.HCl (0.40 g, 2.07mmol) under ice-cooling, and the mixture was stirred for 16 hr whilegradually raising the temperature to room temperature. A solution ofsodium dihydrogenphosphate dihydrate (1.35 g, 8.63 mmol) in water (80mL) was added to the reaction solution, and saturated with sodiumchloride. The mixture was extracted (100 mL×3) with THF, and butanol wasadded to the extract solution. The mixture was concentrated underreduced pressure and diethyl ether was added to the residue. Theprecipitate was collected by filtration and dried to give the titlecompound (1.27 g, quantitative determination, 28% de) as a white powder.

[0481] (2)5-methyl-3(R)-[2-phenyl-1(R)-(sulfomethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0482] The title compound (1.27 g, about 1.73 mmol, 28% de) of Example16 (1) was suspended in a solution of water (25 mL)—methanol (60 mL)—THF(20 mL), and 1N hydrochloric acid (10 mL) was added at room temperature.The mixture was stirred for 7 hr at the same temperature and methanoland THF were distilled away under reduced pressure from the reactionsolution. Water (20 mL) and sodium hydrogencarbonate (1.00 g, 11.90mmol) were added for neutralization. The obtained solution was purifiedby reverse phase column chromatography (Fuji Silysia ChemicalChromatorex ODS DM-1020T: 50 g, water/methanol=100/0, 50/1, 20/1, 10/1,5/1). The eluates from the latter half were collected and methanol wasdistilled away under reduced pressure, followed by freeze-drying. Theobtained freeze-dry product was precipitated from methanol-diethyl etherto give the title compound (0.24 g, 21%) as a white solid.

[0483]¹H-NMR (DMSO-d₆) δ 10.39 (br s, 1H), 9.00-8.20 (br, 1H), 8.41 (d,J=9.0 Hz, 1H), 8.18 (dd, J=6.7, 5.2 Hz, 1H), 7.90-7.75 (m, 4H), 7.31 (d,J=6.9 Hz, 2H), 7.24 (t, J=7.2 Hz, 2H), 7.16 (t, J=7.1 Hz, 1H), 4.75-4.60(m, 1H), 4.08-3.98 (m, 1H), 3.99 (dd, J=12.9, 6.7 Hz, 1H), 3.77 (dd,J=12.9, 5.2 Hz, 1H), 3.50-3.30 (m, 1H), 3.13 (dd, J=13.9, 3.0 Hz, 1H),2.70-2.58 (m, 1H), 2.69 (dd, J=13.9, 11.8 Hz, 1H), 2.58-2.45 (m, 1H),1.29 (t, J=12.0 Hz, 1H), 0.81-0.65 (m, 1H), 0.65-0.50 (m, 1H), 0.54 (d,J=5.1 Hz, 6H).

EXAMPLE 175-methyl-3(R)-[2-phenyl-1(S)-(2-sulfoethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0484]

[0485] Using the title compound of Example 15 (6) and taurine, and inthe same manner as in the method described in Example 15 (7)-(8),synthesis was performed.

[0486]¹H-NMR (DMSO-d₆) δ 10.31 (br s, 1H), 8.59 (s, 1H), 8.38 (d, J=8.7Hz, 1H), 7.85-7.80 (br s, 5H), 7.29-7.25 (m, 2H), 7.08-7.00 (m, 2H),6.77-6.70 (m, 1H), 4.65-4.50 (m, 1H), 3.85-3.74 (m, 1H), 3.52-3.25 (m,3H), 3.07-2.93 (m, 1H), 2.85-2.70 (m, 1H), 2.55-2.40 (m, 3H), 2.19-2.10(m, 1H), 1.55-1.29 (m, 2H), 0.90-0.70 (m, 1H), 0.82 (d, J=6.3 Hz, 3H),0.76 (d, J=6.3 Hz, 3H).

EXAMPLE 185-methyl-3(R)-[2-phenyl-1(R)-(2-sulfoethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0487] [One Kind of Diastereomer of Compound of Example 17]

[0488] Using the title compound of Example 15 (6) and taurine, and inthe same manner as in the method described in Example 16 (1)-(2),synthesis was performed.

[0489]¹H-NMR (DMSO-d₆) δ 10.41 (br s, 1H), 8.70 (s, 1H), 8.43 (d, J=8.4Hz, 1H), 8.08-8.03 (1H, m), 7.83-7.80 (br s, 4H), 7.27-7.14 (m, 5H),4.51-4.44 (m, 1H), 4.00-3.90 (m, 1H), 3.48-3.27 (m, 3H), 3.22-3.04 (m,1H), 2.85-2.55 (m, 5H), 1.65-1.30 (m, 1H), 0.85-0.54 (m, 8H).

EXAMPLE 195-methyl-3(R)-[2-phenyl-1(S)-(3-sulfopropylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0490]

[0491] Using the title compound of Example 15 (6) and3-aminopropanesulfonic acid, and in the same manner as in the methoddescribed in Example 15 (7)-(8), synthesis was performed.

[0492]¹H-NMR (DMSO-d₆) δ 10.30 (s, 1H), 8.59 (s, 1H), 8.33 (d, J=8.7 Hz,1H), 7.85-7.80 (br s, 5H), 7.31-7.27 (m, 2H), 7.07-7.00 (m, 2H),6.73-6.65 (s, 1H), 4.68-4.55 (m, 1H), 3.85-3.73 (m, 1H), 3.25-2.95 (m,3H), 2.84-2.70 (m, 1H), 2.58-2.33 (m, 4H), 2.16-2.04 (m, 1H), 1.80-1.64(m, 2H), 1.55-1.35 (m, 2H), 0.90-0.70 (m, 1H), 0.83 (d, J=6.6 Hz, 3H),0.76 (d, J=6.6 Hz, 3H).

EXAMPLE 205-methyl-3(R)-[2-phenyl-1(R)-(3-sulfopropylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0493] [One Kind of Diastereomer of Compound of Example 19]

[0494] Using the title compound of Example 15 (6) and3-aminopropanesulfonic acid, and in the same manner as in the methoddescribed in Example 16 (1)-(2), synthesis was performed.

[0495]¹H-NMR (DMSO-d₆) δ 10.40 (s, 1H), 8.62 (s, 1H), 8.40 (d, J=8.7 Hz,1H), 7.86-7.73 (br s, 4H), 7.32-7.05 (m, 5H), 4.60-4.48 (m, 1H),4.02-3.89 (m, 1H), 3.82-3.69 (m, 1H), 3.68-3.30 (m, 2H), 3.25-3.00 (m,3H), 2.82-2.70 (m, 2H), 2.69-2.20 (m, 2H), 1.82-1.64 (m, 2H), 1.40-1.20(m, 1H), 0.85-0.41 (m, 8H).

EXAMPLE 215-methyl-3(R)-[2-phenyl-1(S)-(4-sulfobutylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0496]

[0497] Using the title compound of Example 15 (6) and4-aminobutanesulfonic acid, and in the same manner as in the methoddescribed in Example 15 (7)-(8), synthesis was performed.

[0498]¹H-NMR (DMSO-d₆) δ 10.31 (s, 1H), 8.59 (s, 1H), 8.35 (d, J=8.7 Hz,1H), 7.84-7.80 (br s, 5H), 7.31-7.24 (m, 2H), 7.07-7.01 (m, 2H),6.73-6.67 (s, 1H), 4.68-4.58 (m, 1H), 3.84-3.70 (s, 1H), 3.44-3.22 (m,1H), 3.15-2.84 (m, 3H), 2.89-2.71 (m, 1H), 2.51-2.32 (m, 3H), 2.17-2.03(m, 1H), 1.70-1.20 (m, 6H), 0.90-0.70 (m, 1H), 0.82 (d, J=6.6 Hz, 3H),0.76 (d, J=6.6 Hz, 3H).

EXAMPLE 225-methyl-3(R)-[2-phenyl-1(S)-(5-sulfopentylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0499]

[0500] (1) 5-bromopentylsulfonic acid sodium salt

[0501] To a solution of 1,5-dibromopentane (23.2 g, 101 mmol), ethanol(40 mL) and water (40 mL) was dropwise added a solution of sodiumsulfite (4.24 g, 33.6 mmol) in water (15 mL) under heating under refluxover 2 hr. After heating under reflux for 2 hr, the solvent wasdistilled away under reduced pressure and n-hexane/ethanol was added.The precipitated crystals were washed with n-hexane and dried in vacuoto give the title compound (3.81 g, 45%).

[0502]¹H-NMR (DMSO-d₆) δ 3.51 (t, J=6.6 Hz, 2H), 2.46 (t, J=7.5 Hz, 2H),1.90-1.01 (m, 6H).

[0503] (2) 5-aminopentylsulfonic acid

[0504] Aqueous ammonia (50 mL) was added to the title compound (3.80 g,15.0 mmol) of Example 22 (1). The mixture was stirred at roomtemperature for 4 days and dissolved in ethanol. The insoluble materialwas filtered off and the filtrate was concentrated under reducedpressure and dried in vacuo to give the title compound (3.53 g,quantitative determination).

[0505]¹H-NMR (DMSO-d₆) δ 7.90-7.55 (br, 2H), 2.76 (t, J=7.2 Hz, 2H),2.39 (t, J=7.8 Hz, 2H), 1.71-1.05 (m, 6H).

[0506] (3)5-methyl-3(R)-[2-phenyl-1(S)-(5-sulfopentylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid sodium salt

[0507] Using the title compound of Example 15 (6) and the title compoundof Example 22 (2), and in the same manner as in the method described inExample 15 (7)-(8), synthesis was performed.

[0508]¹H-NMR (DMSO-d₆) δ 10.32 (s, 1H), 8.60 (s, 1H), 8.37 (d, J=8.4 Hz,1H), 7.85-7.81 (br s, 5H), 7.77-7.72 (m, 1H), 7.30-7.26 (m, 2H),7.08-7.02 (m, 2H), 6.76-6.70 (s, 1H), 4.70-4.58 (m, 1H), 3.50-3.30 (m,1H), 3.21-2.99 (m, 3H), 2.88-2.69 (m, 1H), 2.58-2.31 (m, 3H), 2.21-2.08(m, 1H), 1.67-1.17 (m, 8H), 0.90-0.70 (m, 1H), 0.82 (d, J=6.3 Hz, 3H),0.76 (d, J=6.6 Hz, 3H).

EXAMPLE 235-methyl-3(R)-[2-phenyl-1(S)-(4-sulfophenylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0509]

[0510] Using the title compound of Example 15 (6) and sulfanilic acid,and in the same manner as in the method described in Example 15 (7)-(8),synthesis was performed.

[0511]¹H-NMR (DMSO-d₆) δ 10.32 (br s, 1H), 10.15 (br s, 1H), 8.90-8.30(br, 1H), 8.53 (d, J=8.4 Hz, 1H), 8.00-7.80 (m, 4H), 7.70-7.50 (m, 4H),7.36 (d, J=7.5 Hz, 2H), 7.07 (t, J=7.5 Hz, 2H), 6.74 (t, J=7.4 Hz, 1H),4.95-4.80 (m, 1H), 3.50-3.25 (m, 1H), 3.10 (dd, J=13.6, 4.5 Hz, 1H),2.86 (dd, J=13.6, 11.1 Hz, 1H), 2.62-2.37 (m, 2H), 2.19 (dd, J=13.8, 3.8Hz, 1H), 1.60-1.20 (m, 2H), 0.95-0.80 (m, 1H), 0.84 (d, J=6.3 Hz, 3H),0.74 (d, J=6.3 Hz, 3H).

EXAMPLE 245-methyl-3(R)-[2-phenyl-1(R)-(4-sulfophenylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic Acid Sodium Salt

[0512] [One Kind of Diastereomer of Compound of Example 23]

[0513] Using the title compound of Example 15 (6) and sulfanilic acid,and in the same manner as in the method described in Example 16 (1)-(2),synthesis was performed.

[0514]¹H-NMR (DMSO-d₆) δ 10.45 (br s, 1H), 10.16 (br s, 1H), 8.68 (br s,1H), 8.61 (d, J=8.4 Hz, 1H), 7.90-7.70 (m, 4H), 7.60 (d, J=8.7 Hz, 2H),7.49 (d, J=8.7 Hz, 2H), 7.34 (d, J=7.2 Hz, 2H), 7.27 (t, J=7.4 Hz, 2H),7.19 (t, J=7.2 Hz, 1H), 4.85-4.65 (m, 1H), 4.04 (dd, J=13.3, 10.8 Hz,1H), 3.42 (dd, J=13.3, 3.2 Hz, 1H), 3.18 (dd, J=13.5, 3.3 Hz, 1H), 2.83(dd, J=13.5, 11.3 Hz, 1H), 2.80-2.40 (m, 2H), 1.50-1.30 (m, 1H),0.95-0.65 (m, 2H), 0.61 (d, J=6.0 Hz, 3H), 0.59 (d, J=6.0 Hz, 3H).

EXAMPLE 25 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(sulfomethylcarbamoyl)ethylcarbamoyl]hexanohydroxamicAcid Sodium Salt

[0515]

[0516] (1) 2-tetrahydropyranyl5-methyl-3(R)-[1(S)-carboxy-2-phenylethylcarbamoyl]-2(R orS)-(2-naphthylmethyl)hexanohydroxamate sodium salt

[0517] Using the title compound of Example 13 (1) and the title compoundof Example 15 (2), and in the same manner as in the method described inExample 15 (3)-(6), synthesis was performed.

[0518] (2) 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(sulfomethylcarbamoyl)ethylcarbamoyl]hexanohydroxamicacid sodium salt

[0519] Using the title compound of Example 25 (1) andaminomethanesulfonic acid, and in the same manner as in the methoddescribed in Example 15 (7)-(8), synthesis was performed.

[0520]¹H-NMR (DMSO-d₆) δ 13.00-9.70 (br, 1H), 8.32 (d, J=8.4 Hz, 1H),8.20-8.07 (br, 1H), 7.85-7.69 (m, 3H), 7.50-7.29 (m, 4H), 7.28-7.19 (m,1H), 7.13-7.00 (s, 2H), 6.99-6.84 (m, 1H), 6.82-6.60 (m, 1H), 4.99-4.68(m, 1H), 4.10-3.94 (m, 1H), 3.93-3.75 (m, 1H), 3.07-2.98 (m, 1H),2.75-2.69 (m, 1H), 2.52-2.30 (m, 3H), 2.29-2.14 (m, 1H), 1.85-1.66 (m,1H), 1.50-1.24 (m, 2H), 0.90-0.70 (m, 1H), 0.85 (d, J=6.3 Hz, 3H), 0.75(d, J=6.3 Hz, 3H).

EXAMPLE 26 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(2-sulfoethylcarbamoyl)ethylcarbamoyl]hexanohydroxamicAcid Sodium Salt

[0521]

[0522] Using the title compound of Example 25 (1) and taurine, and inthe same manner as in the method described in Example 15 (7)-(8),synthesis was performed.

[0523]¹H-NMR (DMSO-d₆) δ 10.15 (br s, 1H), 8.69-8.43 (br s, 1H), 8.38(d, J=8.7 Hz, 1H), 7.94-7.69 (m, 4H), 7.50-7.37 (m, 2H), 7.36-7.24 (m,3H), 7.18-7.03 (m, 2H), 7.02-6.98 (m, 1H), 6.89-6.78 (m, 1H), 4.70-4.56(m, 1H), 3.50-2.78 (m, 3H), 3.18-2.92 (m, 1H), 2.91-2.85 (m, 1H),2.58-2.41 (m, 3H), 2.39-2.10 (m, 1H), 2.00-1.87 (m, 1H), 1.50-1.28 (m,2H), 0.90-0.70 (m, 1H), 0.85 (d, J=6.3 Hz, 3H), 0.77 (d, J=6.3 Hz, 3H).

Experimental Example 1 Inhibitory Effect of Pharmaceutical Agent on LPSin E. coli Culture Supernatant

[0524] One platinum loop of E. coli NIHJ JC-2 strain was inoculated intoa test tube containing heart infusion broth (HIB, 5 mL) and cultured forabout 24 hr. The bacterial culture broth was washed three times bycentrifugation (3000 rpm, 15 min, 20° C., TOMY Seiko, RL-131) using 10mL of fresh HIB medium for one cycle of washing. The washed bacteriawere prepared to an about 10⁷ colony forming unit (CFU)/mL with a freshHIB medium, and 0.2 mL of the prepared bacterial suspension wasinoculated into an Erlenmeyer flask containing a fresh HIB medium (18.8mL) (i.e., to final bacterial concentration of about 10⁵ CFU/mL). Asolution (1 mL) of each compound prepared to a concentration of 2 mM(final concentration of compound 100 μM) was added to the culture brothcontaining the bacteria. Using a shaker (RGR-1 type, manufactured byIWASHIYA, Ltd.), shake culture was conducted at 37° C., and 2 mL ofculture broth after 24 hr was sampled. The sampled culture broth wasfiltered (DISMIC, 0.45 μm, Advantech Toyo) and diluted 10⁵-fold withsterile distilled water. The resulting suspension (200 μL) was added toa limulus reagent (LAL ES, Wako Pure Chemical Industries) and LPSconcentration was measured using Toxinometer MT-285 (Wako Pure ChemicalIndustries) preheated to 37° C.

[0525] The LPS inhibitory ratio of the compound was calculated as aratio of the LPS concentration of the compound addition group relativeto the LPS concentration of the compound non-addition group. As aresult, the inhibitory ratio of the compound of Example 1 was46.5-65.8%. The inhibitory ratio of each compound is shown in thefollowing in Table 1 as a relative ratio to the inhibitory ratio of thecompound of Example 1 as 1.0. TABLE 1 inhibitory effect of compound onLPS in E. coli culture supernatant relative ratio compound of Example 1 1.0 compound of Example 3  0.70 compound of Example 4  0.69 compound ofExample 5  0.80 compound of Example 6  0.69 compound of Example 7  0.79compound of Example 8  0.60 compound of Example 9  0.51 compound ofExample 10 0.87 compound of Example 11 0.74 compound of Example 12 0.85compound of Example 13 0.87 compound of Example 15 1.05 compound ofExample 17 0.78 compound of Example 19 0.67 compound of Example 21 0.79compound of Example 22 0.68 compound of Example 25 0.33 compound ofExample 26 0.54

Experimental Example 2 Inhibitory Effect of Pharmaceutical Agent on LPSthat Increases in Rat Peritonitis Model

[0526] Rat peritonitis (CLP; cecal ligation and puncture) model wasprepared according to the method of Wichterman et al. (J. Surg. Res. 29,189-201 <1980>). That is, a rat fasted overnight was anesthetized withether, and a midline laparotomy was performed and the cecum was exposed.The cecum was ligated with a 3-0 silk thread at its base and perforatedtwo times with an 18G injection needle. The cecum was gently squeezed toextrude feces, which were spread around the abdomen, and the sectionedpart was sutured. The animal was fixed in a Borrmann cage, andphysiological saline or drug solution (2 mg/mL) was continuously givenfrom the tail vein at an administration rate of 2.5 mg/kg/hr with aninfusion pump (22 M, Harvard, 5 mL/kg/hr as a dose).

[0527] After 6 hr of the CLP treatment, the animal was sacrificed withcarbonic acid gas. The abdominal cavity was washed by injectingphosphate buffered saline (PBS; 37° C., 10 mL) and the abdominal cavitywashing containing ascites (PLF; peritoneal lavage fluid) was recovered.The recovery weight of the obtained PLF was measured, and PLF wascentrifuged (1500 rpm for 5 min, 4° C.) to recover supernatant. Theblood taken from the heart was centrifuged (3000 rpm for 10 min, 4° C.)using a serum separation tube, and the serum was recovered. Theconcentration of LPS in the abdominal cavity and serum was measuredusing Toxinometer MT-285 (Waco Pure Chemical Industries) preheated to37° C., after diluting the supernatant and serum of the recovered PLF10⁵-fold and 10²-fold, respectively, with sterile distilled water, andadding 200 μL thereof to a limulus reagent (LAL ES, Waco Pure ChemicalIndustries). The amount of LPS per abdominal cavity was calculated fromamount of recovered abdominal cavity washing (PLF)×LPS concentration ofPLF.

[0528] The LPS inhibitory ratio of the compound was calculated as theratio of LPS concentration of the compound administration group to LPSconcentration of the physiological saline administration group. The LPSinhibitory ratio of each compound in blood and abdominal cavity was asshown in Table 2. TABLE 2 inhibitory effect of compound against increasein LPS in rat peritonitis model LPS inhibitory ratio (%) in blood inabdominal cavity compound of Example 1  79.9 88.3 compound of Example 1081.4 88.1 compound of Example 11 36.2 5.5 compound of Example 13 74.244.7 compound of Example 15 68.2 70.3 compound of Example 17 59.1 14.4compound of Example 19 67.8 89.6 compound of Example 21 55.9 57.1compound of Example 22 21.6 80.7

[0529] From the above-mentioned experimental results, it is clear thatthe sulfonic acid derivative of hydroxamic acid of the present inventionhas an LPS inhibitory action.

Preparation Example 1

[0530] Tablets containing the following ingredients were preparedaccording to a conventional method. Ingredients per tablet Compound ofExample 1 10 mg Lactose 125 mg Cornstarch 75 mg Talc 4 mg Magnesiumstearate 1 mg Total amount 215 mg

Preparation Example 2

[0531] Capsules containing the following ingredients were preparedaccording to a conventional method. Ingredients per capsule Compound ofExample 1 10 mg Lactose 165 mg Cornstarch 20 mg Talc 5 mg weight of onecapsule 200 mg

Preparation Example 3

[0532] Ointment containing the following ingredients was preparedaccording to a conventional method. Ingredients dose Compound of Example1 0.2 g white petrolatum 97.8 g liquid paraffin 2 g total weight 100 g

Preparation Example 4

[0533] Injection containing the following ingredients was preparedaccording to a conventional method. Ingredients dose Compound of Example1 0.2 g sodium chloride 0.9 g distilled water for injection suitableamount total weight 100 g

Preparation Example 5

[0534] Eye drop containing the following ingredients was preparedaccording to a conventional method. Ingredients Compound of Example 10.1 g sodium chloride 0.3 g sterile purified water suitable amount totalweight 100 g

Industrial Applicability

[0535] The sulfonic acid derivative of hydroxamic acid and apharmacologically acceptable salt thereof of the present invention havean LPS inhibitory action, and are useful for the prophylaxis ortreatment of diseases such as sepsis, MOF, chronic articular rheumatism,Crohn's disease, cachexia, myasthenia gravis, systemic lupuserythematodes, asthma, type I diabetes, psoriasis, other autoimmunediseases, inflammatory diseases and the like.

[0536] This application is based on patent application Nos. 219245/2000and 219034/2000 filed in Japan, the contents of which are herebyincorporated by reference. The references cited herein, includingpatents and patent applications, are hereby incorporated in theirentireties by reference, to the extent that they have been disclosedherein.

What is claimed is:
 1. A sulfonic acid derivative of hydroxamic acid ofthe formula (I)

wherein X is hydrogen or a hydroxyl group-protecting group; R¹ ishydrogen, alkyl, arylalkyl, heteroarylalkyl, heteroarylalkylthioalkyl,heteroarylthioalkyl, arylthioalkyl, alkylthioalkyl, arylalkylthioalkyl,phthalimidoalkyl, alkenyl, or —(CH₂)₁-A [1 is an integer of any of 1 to4 and A is a nitrogen-containing 5- or 6-membered hetero ring, which (a)is bonded via a nitrogen atom, (b) optionally comprises, as a furtherhetero atom, at least one kind of atom selected from nitrogen, oxygenand sulfur at a position not adjacent to the bonded nitrogen atom, (c)comprises carbon atoms adjacent to the bonded nitrogen atom, one or bothof which is(are) substituted by oxo, and which (d) is benzocondensed orhas one or more other carbon atoms optionally substituted by lower alkylor oxo, and/or has other nitrogen atom optionally substituted by loweralkyl or phenyl]; R² is hydrogen, alkyl, arylalkyl, heteroarylalkyl,cycloalkyl, cycloalkylalkyl or aryl; Y is O, NR⁷ (R⁷ is as defined forR²) or S; n is an integer of any of 1 to 6; R³ is hydrogen, halogen(fluorine, chlorine, bromine, iodine), hydroxyl group, trifluoromethyl,cyano, nitro, amino, alkyl, alkoxy, acyloxy, carbamoyl, lower alkylaminoor dilower alkylamino group; R⁴ is OR⁸ (R⁸ is hydrogen, lower alkyl,aryl, heteroaryl, arylalkyl or heteroarylalkyl) or NR¹⁰ R¹¹ [R¹⁰ and R¹¹are the same or different and each is hydrogen, lower alkyl, arylalkyl,heteroaryl, heteroarylalkyl or aryl, or R¹⁰ and R¹¹ optionally form anoptionally substituted hetero ring together with the adjacent nitrogenatom]; and said arylalkyl, heteroarylalkyl, heteroarylalkylthioalkyl,heteroarylthioalkyl, arylthioalkyl, arylalkylthioalkyl,phthalimidoalkyl, aryl and heteroaryl optionally have substituents, or apharmacologically acceptable salt thereof.
 2. The sulfonic acidderivative of hydroxamic acid of claim 1, wherein R³ is hydrogen, or apharmacologically acceptable salt thereof.
 3. The sulfonic acidderivative of hydroxamic acid of claim 1 or 2, wherein R⁴ is NHCH₃ orNHC₆H₅, or a pharmacologically acceptable salt thereof.
 4. A sulfonicacid derivative of hydroxamic acid of the formula (II)

wherein X is hydrogen or a hydroxyl group-protecting group; R¹ ishydrogen, alkyl, arylalkyl, heteroarylalkyl, heteroarylalkylthioalkyl,heteroarylthioalkyl, arylthioalkyl, alkylthioalkyl, arylalkylthioalkyl,phthalimidoalkyl, alkenyl, or —(CH₂)₁-A [1 is an integer of any of 1 to4 and A is a nitrogen-containing 5- or 6-membered hetero ring which (a)is bonded via a nitrogen atom, (b) optionally comprises, as a furtherhetero atom, at least one kind of atom selected from nitrogen, oxygenand sulfur at a position not adjacent to the bonded nitrogen atom, (c)comprises carbon atoms adjacent to the bonded nitrogen atom, one or bothof which is(are) substituted by oxo, and which (d) is benzocondensed orhas one or more other carbon atoms optionally substituted by lower alkylor oxo, and/or has other nitrogen atom optionally substituted by loweralkyl or phenyl]; R² is hydrogen, alkyl, arylalkyl, heteroarylalkyl,cycloalkyl, cycloalkylalkyl or aryl; R¹² is a characteristic group ofnatural or non-natural _(α)-amino acid, wherein a functional grouppresent therein is optionally protected; R⁶ is hydrogen, lower alkyl,aryl, heteroaryl, arylalkyl or heteroarylalkyl; Z is alkylene having 1to 6 carbon atoms, phenylene or naphthalene; and said arylalkyl,heteroarylalkyl, heteroarylalkylthioalkyl, heteroarylthioalkyl,arylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, aryl and heteroaryloptionally have substituents, or a pharmacologically acceptable saltthereof.
 5. The sulfonic acid derivative of hydroxamic acid of claim 4,wherein R¹² is benzyl, or a pharmacologically acceptable salt thereof.6. The sulfonic acid derivative of hydroxamic acid of claim 4 or 5,wherein R⁶ is hydrogen, or a pharmacologically acceptable salt thereof.7. The sulfonic acid derivative of hydroxamic acid of any of claims 1 to6, wherein R¹ is phthalimidomethyl, or a pharmacologically acceptablesalt thereof.
 8. The sulfonic acid derivative of hydroxamic acid of anyof claims 1 to 7, wherein R² is isobutyl, or a pharmacologicallyacceptable salt thereof.
 9. A sulfonic acid derivative of hydroxamicacid selected from the group consisting of5-methyl-3(R)-[1(S)-methylcarbamoyl-2-(4-sulfomethoxyphenyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid,5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(2-sulfoethoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid,5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid,5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(4-sulfobutoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid,5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(5-sulfopentoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid,5-methyl-3(R)-[1(S)-methylcarbamoyl-2-(4-sulfomethoxyphenyl)ethylcarbamoyl]-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic acid,5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(2-sulfoethoxy)phenyl]ethylcarbamoyl}-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic acid,5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic acid,5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(4-sulfobutoxy)phenyl]ethylcarbamoyl}-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic acid,5-methyl-3(R)-{1(S)-methylcarbamoyl-2-[4-(5-sulfopentoxy)phenyl]ethylcarbamoyl}-2(Ror S)-(2-naphthylmethyl)hexanohydroxamic acid,5-methyl-3(R)-{1(S)-phenylcarbamoyl-2-[4-(3-sulfopropoxy)phenyl]ethylcarbamoyl}-2(Ror S)-phthalimidomethylhexanohydroxamic acid,5-methyl-3(R)-[2-phenyl-1(S)-(sulfomethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid,5-methyl-3(R)-[2-phenyl-1(S)-(2-sulfoethylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid,5-methyl-3(R)-[2-phenyl-1(S)-(3-sulfopropylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid,5-methyl-3(R)-[2-phenyl-1(S)-(4-sulfobutylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid,5-methyl-3(R)-[2-phenyl-1(S)-(5-sulfopentylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid, 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(sulfomethylcarbamoyl)ethylcarbamoyl]hexanohydroxamicacid, 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(2-sulfoethylcarbamoyl)ethylcarbamoyl]hexanohydroxamicacid, 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(3-sulfopropylcarbamoyl)ethylcarbamoyl]hexanohydroxamicacid, 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(4-sulfobutylcarbamoyl)ethylcarbamoyl]hexanohydroxamicacid, 5-methyl-2(R orS)-(2-naphthylmethyl)-3(R)-[2-phenyl-1(S)-(5-sulfopentylcarbamoyl)ethylcarbamoyl]hexanohydroxamicacid and5-methyl-3(R)-[2-phenyl-1(S)-(4-sulfophenylcarbamoyl)ethylcarbamoyl]-2(Ror S)-phthalimidomethylhexanohydroxamic acid, or a pharmacologicallyacceptable salt thereof.
 10. A compound of the formula (III)

wherein R⁹ is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl;

is a single bond or double bond; R¹³ is, when

is a single bond, hydrogen, alkyl, arylalkyl, heteroarylalkyl,heteroarylalkylthioalkyl, heteroarylthioalkyl, arylthioalkyl,alkylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, alkenyl, —(CH₂)₁-A[1 is an integer of any of 1 to 4 and A is a nitrogen-containing 5- or6-membered hetero ring, which (a) is bonded via a nitrogen atom, (b)optionally comprises, as a further hetero atom, at least one kind ofatom selected from nitrogen, oxygen and sulfur at a position notadjacent to the bonded nitrogen atom, (c) comprises carbon atomsadjacent to the bonded nitrogen atom, one or both of which is(are)substituted by oxo, and which (d) is benzocondensed or has one or moreother carbon atoms optionally substituted by lower alkyl or oxo, and/orhas other nitrogen atom optionally substituted by lower alkyl or phenyl]or —COOR¹⁴ (R¹⁴ is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl),or CH₂ when

is a double bond; R² is hydrogen, alkyl, arylalkyl, heteroarylalkyl,cycloalkyl, cycloalkylalkyl or aryl; Y is O, NR⁷ (R⁷ is as defined forR²) or S; n is an integer of any of 1 to 6; R³ is hydrogen, halogen(fluorine, chlorine, bromine, iodine), hydroxyl group, trifluoromethyl,cyano, nitro, amino, alkyl, alkoxy, acyloxy, carbamoyl, lower alkylaminoor dilower alkylamino group; and R⁴ is OR⁸ (R⁸ is hydrogen, lower alkyl,aryl, heteroaryl, arylalkyl or heteroarylalkyl) or NR¹⁰ R¹¹ [R¹⁰ and R¹¹are the same or different and each is hydrogen, lower alkyl, arylalkyl,heteroaryl, heteroarylalkyl or aryl, or R¹⁰ and R¹¹ optionally form anoptionally substituted hetero ring together with the adjacent nitrogenatom]; or a pharmacologically acceptable salt thereof.
 11. A compound ofthe formula (IV)

wherein R⁹ is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl;

is a single bond or double bond; R¹³ is, when

is a single bond, hydrogen, alkyl, arylalkyl, heteroarylalkyl,heteroarylalkylthioalkyl, heteroarylthioalkyl, arylthioalkyl,alkylthioalkyl, arylalkylthioalkyl, phthalimidoalkyl, alkenyl, —(CH₂)₁-A[1 is an integer of any of 1 to 4 and A is a nitrogen-containing 5- or6-membered hetero ring, which (a) is bonded via a nitrogen atom, (b)optionally comprises, as a further hetero atom, at least one kind ofatom selected from nitrogen, oxygen and sulfur at a position notadjacent to the bonded nitrogen atom, (c) comprises carbon atomsadjacent to the bonded nitrogen atom, one or both of which is(are)substituted by oxo, and which (d) is benzocondensed or has one or moreother carbon atoms optionally substituted by lower alkyl or oxo, and/orhas other nitrogen atom optionally substituted by lower alkyl or phenyl]or —COOR¹⁴ (R¹⁴ is hydrogen, alkyl, arylalkyl, heteroarylalkyl or aryl),or CH₂ when

is a double bond; R² is hydrogen, alkyl, arylalkyl, heteroarylalkyl,cycloalkyl, cycloalkylalkyl or aryl; R¹² is a characteristic group ofnatural or non-natural _(α)-amino acid, wherein a functional grouppresent therein is optionally protected; R⁶ is hydrogen, lower alkyl,aryl, heteroaryl, arylalkyl or heteroarylalkyl; Z is alkylene having 1to 6 carbon atoms, phenylene or naphthalene; or a pharmacologicallyacceptable salt thereof.
 12. A pharmaceutical composition comprising thesulfonic acid derivative of hydroxamic acid of any of claims 1 to 9 or apharmacologically acceptable salt thereof, and a pharmacologicallyacceptable carrier.
 13. An LPS inhibitor comprising the sulfonic acidderivative of hydroxamic acid of any of claims 1 to 9 or apharmacologically acceptable salt thereof as an active ingredient.